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Pancreatic Neoplasms: HELP
Articles by Marina Pajic
Based on 39 articles published since 2010
(Why 39 articles?)
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Between 2010 and 2020, M. Pajic wrote the following 39 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Editorial Transient targeting of the pancreatic cancer stroma as a 'fine-tuned' anti-tumor and anti-metastatic therapy. 2017

Vennin, Claire / Cox, Thomas R / Pajic, Marina / Timpson, Paul. ·Paul Timpson and Marina Pajic: The Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW & The Kinghorn Cancer Centre, Cancer Division, Australia and St Vincent's Clinical School, Faculty of Medicine, University of NSW, Australia. ·Oncotarget · Pubmed #29156669.

ABSTRACT: -- No abstract --

2 Review Rho-ROCK Signaling in Normal Physiology and as a Key Player in Shaping the Tumor Microenvironment. 2020

Porazinski, Sean / Parkin, Ashleigh / Pajic, Marina. ·Personalised Cancer Therapeutics Lab, The Kinghorn Cancer Centre, Sydney, NSW, Australia. · Faculty of Medicine, St Vincent's Clinical School, University of NSW, Sydney, NSW, Australia. · Personalised Cancer Therapeutics Lab, The Kinghorn Cancer Centre, Sydney, NSW, Australia. m.pajic@garvan.org.au. · Faculty of Medicine, St Vincent's Clinical School, University of NSW, Sydney, NSW, Australia. m.pajic@garvan.org.au. ·Adv Exp Med Biol · Pubmed #32030687.

ABSTRACT: The Rho-ROCK signaling network has a range of specialized functions of key biological importance, including control of essential developmental processes such as morphogenesis and physiological processes including homeostasis, immunity, and wound healing. Deregulation of Rho-ROCK signaling actively contributes to multiple pathological conditions, and plays a major role in cancer development and progression. This dynamic network is critical in modulating the intricate communication between tumor cells, surrounding diverse stromal cells and the matrix, shaping the ever-changing microenvironment of aggressive tumors. In this chapter, we overview the complex regulation of the Rho-ROCK signaling axis, its role in health and disease, and analyze progress made with key approaches targeting the Rho-ROCK pathway for therapeutic benefit. Finally, we conclude by outlining likely future trends and key questions in the field of Rho-ROCK research, in particular surrounding Rho-ROCK signaling within the tumor microenvironment.

3 Review Targeting the complexity of Src signalling in the tumour microenvironment of pancreatic cancer: from mechanism to therapy. 2019

Parkin, Ashleigh / Man, Jennifer / Timpson, Paul / Pajic, Marina. ·The Kinghorn Cancer Centre, The Garvan Institute of Medical Research, Sydney, Australia. · Faculty of Medicine, St Vincent's Clinical School, University of NSW, Sydney, Australia. ·FEBS J · Pubmed #31330086.

ABSTRACT: Pancreatic cancer, a disease with extremely poor prognosis, has been notoriously resistant to virtually all forms of treatment. The dynamic crosstalk that occurs between tumour cells and the surrounding stroma, frequently mediated by intricate Src/FAK signalling, is increasingly recognised as a key player in pancreatic tumourigenesis, disease progression and therapeutic resistance. These important cues are fundamental for defining the invasive potential of pancreatic tumours, and several components of the Src and downstream effector signalling have been proposed as potent anticancer therapeutic targets. Consequently, numerous agents that block this complex network are being extensively investigated as potential antiinvasive and antimetastatic therapeutic agents for this disease. In this review, we will discuss the latest evidence of Src signalling in PDAC progression, fibrotic response and resistance to therapy. We will examine future opportunities for the development and implementation of more effective combination regimens, targeting key components of the oncogenic Src signalling axis, and in the context of a precision medicine-guided approach.

4 Review The Evolving Understanding of the Molecular and Therapeutic Landscape of Pancreatic Ductal Adenocarcinoma. 2018

Parkin, Ashleigh / Man, Jennifer / Chou, Angela / Nagrial, Adnan M / Samra, Jaswinder / Gill, Anthony J / Timpson, Paul / Pajic, Marina. ·The Kinghorn Cancer Centre, The Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, Sydney, NSW 2010, Australia. a.parkin@garvan.org.au. · The Kinghorn Cancer Centre, The Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, Sydney, NSW 2010, Australia. j.man@garvan.org.au. · The Kinghorn Cancer Centre, The Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, Sydney, NSW 2010, Australia. a.chou@garvan.org.au. · University of Sydney, Sydney, NSW 2006, Australia. a.chou@garvan.org.au. · The Kinghorn Cancer Centre, The Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, Sydney, NSW 2010, Australia. Adnan.Nagrial@health.nsw.gov.au. · Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney, NSW 2145, Australia. Adnan.Nagrial@health.nsw.gov.au. · Department of Surgery, Royal North Shore Hospital, St Leonards, Sydney, NSW 2065, Australia. jas.samra@bigpond.com. · The Kinghorn Cancer Centre, The Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, Sydney, NSW 2010, Australia. Anthony.Gill@health.nsw.gov.au. · University of Sydney, Sydney, NSW 2006, Australia. Anthony.Gill@health.nsw.gov.au. · Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards, Sydney, NSW 2065, Australia. Anthony.Gill@health.nsw.gov.au. · Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, St Leonards, NSW 2065, Australia. Anthony.Gill@health.nsw.gov.au. · The Kinghorn Cancer Centre, The Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, Sydney, NSW 2010, Australia. p.timpson@garvan.org.au. · St Vincent's Clinical School, Faculty of Medicine, University of NSW, Sydney, NSW 2010, Australia. p.timpson@garvan.org.au. · The Kinghorn Cancer Centre, The Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, Sydney, NSW 2010, Australia. m.pajic@garvan.org.au. · St Vincent's Clinical School, Faculty of Medicine, University of NSW, Sydney, NSW 2010, Australia. m.pajic@garvan.org.au. ·Diseases · Pubmed #30428574.

ABSTRACT: Pancreatic cancer is the third leading cause of cancer-related deaths, characterised by poor survival, marked molecular heterogeneity and high intrinsic and acquired chemoresistance. Only 10⁻20% of pancreatic cancer patients present with surgically resectable disease and even then, 80% die within 5 years. Our increasing understanding of the genomic heterogeneity of cancer suggests that the failure of definitive clinical trials to demonstrate efficacy in the majority of cases is likely due to the low proportion of responsive molecular subtypes. As a consequence, novel treatment strategies to approach this disease are urgently needed. Significant developments in the field of precision oncology have led to increasing molecular stratification of cancers into subtypes, where individual cancers are selected for optimal therapy depending on their molecular or genomic fingerprint. This review provides an overview of the current status of clinically used and emerging treatment strategies, and discusses the advances in and the potential for the implementation of precision medicine in this highly lethal malignancy, for which there are currently no curative systemic therapies.

5 Review Reshaping the Tumor Stroma for Treatment of Pancreatic Cancer. 2018

Vennin, Claire / Murphy, Kendelle J / Morton, Jennifer P / Cox, Thomas R / Pajic, Marina / Timpson, Paul. ·The Garvan Institute of Medical Research, Sydney, New South Wales, Australia; The Kinghorn Cancer Center, Sydney, New South Wales, Australia; St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia. · Cancer Research UK, The Beatson Institute for Cancer Research, Glasgow, Scotland, United Kingdom. · The Garvan Institute of Medical Research, Sydney, New South Wales, Australia; The Kinghorn Cancer Center, Sydney, New South Wales, Australia; St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia. Electronic address: m.pajic@garvan.org.au. · The Garvan Institute of Medical Research, Sydney, New South Wales, Australia; The Kinghorn Cancer Center, Sydney, New South Wales, Australia; St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia. Electronic address: p.timpson@garvan.org.au. ·Gastroenterology · Pubmed #29287624.

ABSTRACT: Pancreatic cancer is accompanied by a fibrotic reaction that alters interactions between tumor cells and the stroma to promote tumor progression. Consequently, strategies to target the tumor stroma might be used to treat patients with pancreatic cancer. We review recently developed approaches for reshaping the pancreatic tumor stroma and discuss how these might improve patient outcomes. We also describe relationships between the pancreatic tumor extracellular matrix, the vasculature, the immune system, and metabolism, and discuss the implications for the development of stromal compartment-specific therapies.

6 Review Second-line treatment in inoperable pancreatic adenocarcinoma: A systematic review and synthesis of all clinical trials. 2015

Nagrial, Adnan M / Chin, Venessa T / Sjoquist, Katrin M / Pajic, Marina / Horvath, Lisa G / Biankin, Andrew V / Yip, Desmond. ·The Kinghorn Cancer Centre, 370 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia; The Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia. Electronic address: a.nagrial@garvan.org.au. · The Kinghorn Cancer Centre, 370 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia; The Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia. · NHMRC Clinical Trials Centre, University of Sydney, NSW, Australia; Cancer Care Centre, St. George Hospital, Kogarah, NSW, Australia. · The Kinghorn Cancer Centre, 370 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia; The Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia; St. Vincents's Clinical School, Faculty of Medicine, University of NSW, Australia. · The Kinghorn Cancer Centre, 370 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia; The Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia; Department of Medical Oncology, Chris O'Brien Lifehouse, Sydney, NSW 2050, Australia. · The Kinghorn Cancer Centre, 370 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia; The Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia; Department of Surgery, Bankstown Hospital, Eldridge Road, Bankstown, Sydney, NSW 2200, Australia; South Western Sydney Clinical School, Faculty of Medicine, University of NSW, Liverpool, NSW 2170, Australia; Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1BD, Scotland, UK; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, Scotland G4 0SF, UK. · Department of Medical Oncology, The Canberra Hospital, Garran, ACT, Australia; ANU Medical School, Australian National University, Acton, ACT, Australia. ·Crit Rev Oncol Hematol · Pubmed #26481952.

ABSTRACT: There remains uncertainty regarding the optimal second-line chemotherapy in advanced pancreatic ductal adenocarcinoma (PDAC). The current recommendation of 5-fluorouracil and oxaliplatin may not be relevant in current practice, as FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan and oxaliplatin) has become a more popular first line therapy in fit patients. The majority of studies in this setting are single-arm Phase II trials with significant heterogeneity of patient populations, treatments and outcomes. In this review, we sought to systematically review and synthesise all prospective data available for the second-line treatment of advanced PDAC.

7 Review Personalising pancreas cancer treatment: When tissue is the issue. 2014

Sjoquist, Katrin M / Chin, Venessa T / Chantrill, Lorraine A / O'Connor, Chelsie / Hemmings, Chris / Chang, David K / Chou, Angela / Pajic, Marina / Johns, Amber L / Nagrial, Adnan M / Biankin, Andrew V / Yip, Desmond. ·Katrin M Sjoquist, NHMRC Clinical Trials Centre, University of Sydney, Sydney NSW 1450, Australia. ·World J Gastroenterol · Pubmed #24976722.

ABSTRACT: The treatment of advanced pancreatic cancer has not moved much beyond single agent gemcitabine until recently when protocols such as FOLFIRINOX (fluorouracil, leucovorin, irinotecan and oxaliplatin) and nab-paclitaxel-gemcitabine have demonstrated some improved outcomes. Advances in technology especially in massively parallel genome sequencing has progressed our understanding of the biology of pancreatic cancer especially the candidate signalling pathways that are involved in tumourogenesis and disease course. This has allowed identification of potentially actionable mutations that may be targeted by new biological agents. The heterogeneity of pancreatic cancer makes tumour tissue collection important with the aim of being able to personalise therapies for the individual as opposed to a one size fits all approach to treatment of the condition. This paper reviews the developments in this area of translational research and the ongoing clinical studies that will attempt to move this into the everyday oncology practice.

8 Review Understanding pancreatic cancer genomes. 2013

Cowley, Mark J / Chang, David K / Pajic, Marina / Johns, Amber L / Waddell, Nicola / Grimmond, Sean M / Biankin, Andrew V. ·The Kinghorn Cancer Centre, 370 Victoria St, Darlinghurst, Australia; Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, Sydney, NSW, 2010, Australia. ·J Hepatobiliary Pancreat Sci · Pubmed #23660961.

ABSTRACT: Pancreatic cancer is the fourth leading cause of cancer death in our society, with a mortality that virtually parallels its incidence, a median survival of <12 months even with maximal therapy, and a 5-year survival rate of <5 %. The diversity of clinical outcomes and the molecular heterogeneity of histopathologically similar cancer types, incomplete knowledge of the genomic aberrations that drive carcinogenesis and the lack of therapeutics that specifically target most known genomic aberrations necessitates large-scale detailed analysis of cancer genomes to identify novel potential therapeutic strategies. As part of the International Cancer Genome Consortium (ICGC), the Australian Pancreatic Cancer Genome Initiative (APGI) used exomic sequencing and copy number analysis to define genomic aberrations that characterize a large, clinically focused, prospectively accrued cohort of patients with pancreatic cancer. The cohort consisted of early (clinical stages I and II) non-pre-treated patients with pancreatic ductal adenocarcinoma who underwent operative resection with curative intent. We devised approaches to adjust for low epithelial content in primary tumours and to define the genomic landscape of pancreatic cancer to identify novel candidate driver genes and mechanisms. We aim to develop stratified, molecular phenotype-guided therapeutic strategies using existing therapeutics that are either rescued, repurposed, in development, or are known to be effective in an undefined subgroup of PC patients. These are then tested in primary patient-derived xenografts and cell lines from the above deeply characterized cohort. In addition, we return information to treating clinicians that influences patient care and are launching a clinical trial called IMPaCT (Individualized Molecular Pancreatic Cancer Therapy). This umbrella design trial randomizes patients with metastatic disease to either standard first-line therapy with gemcitabine, or a molecular phenotype-guided approach using next-generation sequencing strategies to screen for actionable mutations defined through the ICGC effort.

9 Clinical Trial Precision Medicine for Advanced Pancreas Cancer: The Individualized Molecular Pancreatic Cancer Therapy (IMPaCT) Trial. 2015

Chantrill, Lorraine A / Nagrial, Adnan M / Watson, Clare / Johns, Amber L / Martyn-Smith, Mona / Simpson, Skye / Mead, Scott / Jones, Marc D / Samra, Jaswinder S / Gill, Anthony J / Watson, Nicole / Chin, Venessa T / Humphris, Jeremy L / Chou, Angela / Brown, Belinda / Morey, Adrienne / Pajic, Marina / Grimmond, Sean M / Chang, David K / Thomas, David / Sebastian, Lucille / Sjoquist, Katrin / Yip, Sonia / Pavlakis, Nick / Asghari, Ray / Harvey, Sandra / Grimison, Peter / Simes, John / Biankin, Andrew V / Anonymous5550827 / Anonymous5560827. ·The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, Sydney, New South Wales, Australia. Macarthur Cancer Therapy Centre, Campbelltown, New South Wales, Australia. Sydney Catalyst Translational Cancer Research Centre, University of Sydney, Camperdown, New South Wales, Australia. andrew.biankin@glasgow.ac.uk l.chantrill@garvan.org.au. · The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, Sydney, New South Wales, Australia. Sydney Catalyst Translational Cancer Research Centre, University of Sydney, Camperdown, New South Wales, Australia. Crown Princess Mary Cancer Centre, Westmead, New South Wales, Australia. · The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, Sydney, New South Wales, Australia. · The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, Sydney, New South Wales, Australia. Prince of Wales Hospital, Randwick, New South Wales, Australia. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland. · University of Sydney, New South Wales, Australia. Macquarie University Hospital, Sydney, New South Wales, Australia. · Department of Anatomical Pathology, Royal North Shore Hospital, Sydney, New South Wales, Australia. · The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, Sydney, New South Wales, Australia. Sydney Catalyst Translational Cancer Research Centre, University of Sydney, Camperdown, New South Wales, Australia. · The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, Sydney, New South Wales, Australia. Department of Anatomical Pathology, St. Vincent's Hospital, Darlinghurst, Sydney, New South Wales, Australia. · Department of Anatomical Pathology, St. Vincent's Hospital, Darlinghurst, Sydney, New South Wales, Australia. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland. Department of Surgery, Bankstown Hospital, Sydney, New South Wales, Australia. South Western Sydney Clinical School, Faculty of Medicine, University of NSW, Liverpool, New South Wales, Australia. West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom. · NHMRC Clinical Trials Centre, University of Sydney, Camperdown, New South Wales, Australia. · Sydney Catalyst Translational Cancer Research Centre, University of Sydney, Camperdown, New South Wales, Australia. NHMRC Clinical Trials Centre, University of Sydney, Camperdown, New South Wales, Australia. · Northern Sydney Cancer Centre, Royal North Shore Hospital, New South Wales, Australia. · Bankstown Cancer Centre, Bankstown, New South Wales, Australia. · Sydney Catalyst Translational Cancer Research Centre, University of Sydney, Camperdown, New South Wales, Australia. Chris O'Brien Lifehouse, Camperdown, New South Wales, Australia. · Sydney Catalyst Translational Cancer Research Centre, University of Sydney, Camperdown, New South Wales, Australia. NHMRC Clinical Trials Centre, University of Sydney, Camperdown, New South Wales, Australia. Chris O'Brien Lifehouse, Camperdown, New South Wales, Australia. · The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, Sydney, New South Wales, Australia. Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland. Department of Surgery, Bankstown Hospital, Sydney, New South Wales, Australia. South Western Sydney Clinical School, Faculty of Medicine, University of NSW, Liverpool, New South Wales, Australia. West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom. andrew.biankin@glasgow.ac.uk l.chantrill@garvan.org.au. ·Clin Cancer Res · Pubmed #25896973.

ABSTRACT: PURPOSE: Personalized medicine strategies using genomic profiling are particularly pertinent for pancreas cancer. The Individualized Molecular Pancreatic Cancer Therapy (IMPaCT) trial was initially designed to exploit results from genome sequencing of pancreatic cancer under the auspices of the International Cancer Genome Consortium (ICGC) in Australia. Sequencing revealed small subsets of patients with aberrations in their tumor genome that could be targeted with currently available therapies. EXPERIMENTAL DESIGN: The pilot stage of the IMPaCT trial assessed the feasibility of acquiring suitable tumor specimens for molecular analysis and returning high-quality actionable genomic data within a clinically acceptable timeframe. We screened for three molecular targets: HER2 amplification; KRAS wild-type; and mutations in DNA damage repair pathways (BRCA1, BRCA2, PALB2, ATM). RESULTS: Tumor biopsy and archived tumor samples were collected from 93 patients and 76 were screened. To date 22 candidate cases have been identified: 14 KRAS wild-type, 5 cases of HER2 amplification, 2 mutations in BRCA2, and 1 ATM mutation. Median time from consent to the return of validated results was 21.5 days. An inability to obtain a biopsy or insufficient tumor content in the available specimen were common reasons for patient exclusion from molecular analysis while deteriorating performance status prohibited a number of patients from proceeding in the study. CONCLUSIONS: Documenting the feasibility of acquiring and screening biospecimens for actionable molecular targets in real time will aid other groups embarking on similar trials. Key elements include the need to better prescreen patients, screen more patients, and offer more attractive clinical trial options.

10 Article Targeting ROCK activity to disrupt and prime pancreatic cancer for chemotherapy. 2020

Vennin, Claire / Rath, Nicola / Pajic, Marina / Olson, Michael F / Timpson, Paul. ·The Garvan Institute of Medical Research, Sydney, Australia. · The Kinghorn Cancer Centre, Sydney, Australia. · St Vincent's Clinical School, University of New South Wales, Sydney Australia. · Cancer Research UK Beatson Institute, Glasgow, United Kingdom. · Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom. ·Small GTPases · Pubmed #28972449.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease; the identification of novel targets and development of effective treatment strategies are urgently needed to improve patient outcomes. Remodeling of the pancreatic stroma occurs during PDAC development, which drives disease progression and impairs responses to therapy. The actomyosin regulatory ROCK1 and ROCK2 kinases govern cell motility and contractility, and have been suggested to be potential targets for cancer therapy, particularly to reduce the metastatic spread of tumor cells. However, ROCK inhibitors are not currently used for cancer patient treatment, largely due to the overwhelming challenge faced in the development of anti-metastatic drugs, and a lack of clarity as to the cancer types most likely to benefit from ROCK inhibitor therapy. In 2 recent publications, we discovered that ROCK1 and ROCK2 expression were increased in PDAC, and that increased ROCK activity was associated with reduced survival and PDAC progression by enabling extracellular matrix (ECM) remodeling and invasive growth of pancreatic cancer cells. We also used intravital imaging to optimize ROCK inhibition using the pharmacological ROCK inhibitor fasudil (HA-1077), and demonstrated that short-term ROCK targeting, or 'priming', improved chemotherapy efficacy, disrupted cancer cell collective movement, and impaired metastasis. This body of work strongly indicates that the use of ROCK inhibitors in pancreatic cancer therapy as 'priming' agents warrants further consideration, and provides insights as to how transient mechanical manipulation, or fine-tuning the ECM, rather than chronic stromal ablation might be beneficial for improving chemotherapeutic efficacy in the treatment of this deadly disease.

11 Article CAF hierarchy driven by pancreatic cancer cell p53-status creates a pro-metastatic and chemoresistant environment via perlecan. 2019

Vennin, Claire / Mélénec, Pauline / Rouet, Romain / Nobis, Max / Cazet, Aurélie S / Murphy, Kendelle J / Herrmann, David / Reed, Daniel A / Lucas, Morghan C / Warren, Sean C / Elgundi, Zehra / Pinese, Mark / Kalna, Gabriella / Roden, Daniel / Samuel, Monisha / Zaratzian, Anaiis / Grey, Shane T / Da Silva, Andrew / Leung, Wilfred / Anonymous4001119 / Mathivanan, Suresh / Wang, Yingxiao / Braithwaite, Anthony W / Christ, Daniel / Benda, Ales / Parkin, Ashleigh / Phillips, Phoebe A / Whitelock, John M / Gill, Anthony J / Sansom, Owen J / Croucher, David R / Parker, Benjamin L / Pajic, Marina / Morton, Jennifer P / Cox, Thomas R / Timpson, Paul. ·The Garvan Institute of Medical Research & The Kinghorn Cancer Centre, Sydney, NSW, 2010, Australia. · St Vincent's Clinical School, Faculty of Medicine, University of New South Wales Sydney, Sydney, NSW, 2010, Australia. · Molecular Pathology department, the Netherlands Cancer Institute, Amsterdam, 1066CX, the Netherlands. · Graduate school of Biomedical Engineering, University of New South Wales Sydney, Sydney, NSW, 2052, Australia. · Cancer Research UK Beatson Institute, Glasgow Scotland, G61 BD, UK. · Department of Physiology, Anatomy and Microbiology, School of Life Sciences, La Trobe University, Bundoora, VIC, 3086, Australia. · Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA. · Department of Bioengineering, Institute of Engineering in Medicine, University of California, San Diego, CA, 92121, USA. · Children's Medical Research Institute, University of Sydney, Sydney, NSW, 2006, Australia. · Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, 9054, New Zealand. · Maurice Wilkins Centre, University of Otago, Dunedin, 9054, New Zealand. · Biomedical imaging facility, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia. · Pancreatic Cancer Translational Research Group, Lowy Cancer Research Centre, School of Medical Sciences, University of New South Wales, Sydney, NSW, 2052, Australia. · Australian Centre for Nanomedicine, University of New South Wales, Sydney, NSW, 2052, Australia. · Sydney Medical School, University of Sydney, Sydney, NSW, 2006, Australia. · NSW Health Pathology, Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards, Sydney, NSW, 2065, Australia. · Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, St Leonards, NSW, 2065, Australia. · Schools of Life and Environmental Sciences, the Charles Perkin Centre, the University of Sydney, Sydney, NSW, 2006, Australia. · The Garvan Institute of Medical Research & The Kinghorn Cancer Centre, Sydney, NSW, 2010, Australia. t.cox@garvan.org.au. · St Vincent's Clinical School, Faculty of Medicine, University of New South Wales Sydney, Sydney, NSW, 2010, Australia. t.cox@garvan.org.au. · The Garvan Institute of Medical Research & The Kinghorn Cancer Centre, Sydney, NSW, 2010, Australia. p.timpson@garvan.org.au. · St Vincent's Clinical School, Faculty of Medicine, University of New South Wales Sydney, Sydney, NSW, 2010, Australia. p.timpson@garvan.org.au. ·Nat Commun · Pubmed #31406163.

ABSTRACT: Heterogeneous subtypes of cancer-associated fibroblasts (CAFs) coexist within pancreatic cancer tissues and can both promote and restrain disease progression. Here, we interrogate how cancer cells harboring distinct alterations in p53 manipulate CAFs. We reveal the existence of a p53-driven hierarchy, where cancer cells with a gain-of-function (GOF) mutant p53 educate a dominant population of CAFs that establish a pro-metastatic environment for GOF and null p53 cancer cells alike. We also demonstrate that CAFs educated by null p53 cancer cells may be reprogrammed by either GOF mutant p53 cells or their CAFs. We identify perlecan as a key component of this pro-metastatic environment. Using intravital imaging, we observe that these dominant CAFs delay cancer cell response to chemotherapy. Lastly, we reveal that depleting perlecan in the stroma combined with chemotherapy prolongs mouse survival, supporting it as a potential target for anti-stromal therapies in pancreatic cancer.

12 Article PAK inhibition by PF-3758309 enhanced the sensitivity of multiple chemotherapeutic reagents in patient-derived pancreatic cancer cell lines. 2019

Wang, Kai / Huynh, Nhi / Wang, Xiao / Pajic, Marina / Parkin, Ashleigh / Man, Jennifer / Baldwin, Graham S / Nikfarjam, Mehrdad / He, Hong. ·Department of Surgery, University of Melbourne, Austin Health Studley Road, Heidelberg, Victoria 3084, Australia. · The Kinghorn Cancer Centre, The Garvan Institute of Medical Research 384 Victoria St, Darlinghurst, Sydney, NSW 2010, Australia. · St Vincent's Clinical School, Faculty of Medicine, University of NSW Australia. ·Am J Transl Res · Pubmed #31312349.

ABSTRACT: BACKGROUND/OBJECTIVE: Pancreatic ductal adenocarcinoma (PDA) remains the most lethal malignancy due to lack of an effective treatment. P21-activated kinases (PAKs) play a key role not only in cell proliferation and migration, but also in mediating chemo-resistance in PDA. The aim of this study was to investigate the combined effect of a PAK inhibitor PF-3758309 with multiple chemotherapeutic reagents on a panel of patient-derived PDA cell lines, and potential mechanisms involved. METHODS: Cells were treated with PF-3758309 plus or minus gemcitabine, 5-fluorouracil (5-FU) or abraxane, and cell growth was determined using a cell proliferation assay kit. Protein expression profiles were measured by Western blot. PDA cells were subcutaneously injected into the flanks of SCID mice which were then treated with saline, gemcitabine, PF-3758309, gemcitabine plus PF-3758309 or abraxane. Tumour growth was measured by volume and weight. RESULTS: PAK1 was correlated with CK19 expression, and PAK4 with α-SMA and palladin expression. Combination of PF-3758309 with 5-FU, gemcitabine or abraxane further suppressed cell growth of patient-derived PDA cell lines CONCLUSIONS: PAK inhibitor PF-3758309 can enhance anti-tumour effects of multiple chemotherapeutic reagents on a panel of patient-derived PDA cell lines. Combination of PF-3758309 with gemcitabine achieves comparable efficacy to combination of gemcitabine with abraxane, and thus provides a potential targeted therapy in the management of PDA.

13 Article ATRX loss is an independent predictor of poor survival in pancreatic neuroendocrine tumors. 2018

Chou, Angela / Itchins, Malinda / de Reuver, Philip R / Arena, Jennifer / Clarkson, Adele / Sheen, Amy / Sioson, Loretta / Cheung, Veronica / Perren, Aurel / Nahm, Christopher / Mittal, Anubhav / Samra, Jaswinder S / Pajic, Marina / Gill, Anthony J. ·Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards, NSW 2065, Australia; University of Sydney, Sydney, NSW 2006, Australia; Department of Anatomical Pathology, SYDPATH, St Vincent's Hospital, Darlinghurst, NSW 2010, Australia; The Kinghorn Cancer Centre and Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia. · University of Sydney, Sydney, NSW 2006, Australia; Department of Medical Oncology, Royal North Shore Hospital, St Leonards, NSW 2065, Australia. · Department of Surgery, Radboud University Medical Center, Nijmegen 6525, The Netherlands; Department of Upper Gastrointestinal Surgery, Royal North Shore Hospital, St Leonards, NSW 2065, Australia. · Department of Upper Gastrointestinal Surgery, Royal North Shore Hospital, St Leonards, NSW 2065, Australia. · Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards, NSW 2065, Australia; NSW Health Pathology, Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards, NSW 2065, Australia. · Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards, NSW 2065, Australia. · Institute of Pathology, University of Bern, Bern 3012, Switzerland. · University of Sydney, Sydney, NSW 2006, Australia; Department of Upper Gastrointestinal Surgery, Royal North Shore Hospital, St Leonards, NSW 2065, Australia. · The Kinghorn Cancer Centre and Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia. · Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards, NSW 2065, Australia; University of Sydney, Sydney, NSW 2006, Australia; NSW Health Pathology, Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards, NSW 2065, Australia. Electronic address: affgill@med.usyd.edu.au. ·Hum Pathol · Pubmed #30081149.

ABSTRACT: Pancreatic neuroendocrine tumors (PanNETs) are rare neoplasms accounting for 1% to 2% of all pancreatic tumors. The biological behavior of PanNETs is heterogeneous and unpredictable, adding to the difficulties of clinical management. The DAXX (death domain associated protein) and ATRX (α-thalassemia/mental retardation syndrome X-linked) genes encode proteins involved in SWI/SNF-like chromatin remodeling. Somatic inactivating mutations in DAXX and ATRX are frequent in PanNETs, mutually exclusive, and associated with telomere dysfunction, resulting in genomic instability and alternate lengthening of telomeres. We sought to assess the clinical significance of the loss of the ATRX and DAXX proteins as determined by immunohistochemistry (IHC) in patients with PanNET. From an unselected cohort of 105 patients, we found ATRX loss in 10 tumors (9.5%) and DAXX loss in 16 (15.2%). DAXX and ATRX losses were confirmed mutually exclusive and associated with other adverse clinicopathological variables and poor survival in univariate analysis. In addition, ATRX loss was also associated with higher AJCC stage and infiltrative tumor borders. However, only ATRX loss, lymphovascular invasion, and perineural spread were independent predictors of poor overall survival in multivariate analysis. In conclusion, loss of expression of ATRX as determined by IHC is a useful independent predictor of poor overall survival in PanNETs. Given its relative availability, ATRX loss as determined by IHC may have a role in routine clinical practice to refine prognostication in patients with PanNET.

14 Article Intravital Imaging to Monitor Therapeutic Response in Moving Hypoxic Regions Resistant to PI3K Pathway Targeting in Pancreatic Cancer. 2018

Conway, James R W / Warren, Sean C / Herrmann, David / Murphy, Kendelle J / Cazet, Aurélie S / Vennin, Claire / Shearer, Robert F / Killen, Monica J / Magenau, Astrid / Mélénec, Pauline / Pinese, Mark / Nobis, Max / Zaratzian, Anaiis / Boulghourjian, Alice / Da Silva, Andrew M / Del Monte-Nieto, Gonzalo / Adam, Arne S A / Harvey, Richard P / Haigh, Jody J / Wang, Yingxiao / Croucher, David R / Sansom, Owen J / Pajic, Marina / Caldon, C Elizabeth / Morton, Jennifer P / Timpson, Paul. ·Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Cancer Division, Sydney, NSW 2010, Australia. · Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Cancer Division, Sydney, NSW 2010, Australia; St Vincent's Clinical School, Faculty of Medicine, University of NSW, Sydney, NSW 2010, Australia. · St Vincent's Clinical School, Faculty of Medicine, University of NSW, Sydney, NSW 2010, Australia; Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research Institute, Sydney, NSW 2010, Australia. · Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research Institute, Sydney, NSW 2010, Australia. · St Vincent's Clinical School, Faculty of Medicine, University of NSW, Sydney, NSW 2010, Australia; Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research Institute, Sydney, NSW 2010, Australia; School of Biotechnology and Biomolecular Science, University of New South Wales, Sydney, NSW 2033, Australia. · Australian Centre for Blood Diseases, Monash University, Melbourne, VIC 3004, Australia. · Department of Bioengineering, University of Illinois, Urbana-Champaign, Urbana, IL 61801, USA. · Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Cancer Division, Sydney, NSW 2010, Australia; St Vincent's Clinical School, Faculty of Medicine, University of NSW, Sydney, NSW 2010, Australia; School of Medicine and Medical Science, University College Dublin, Belfield, Dublin 4, Ireland. · Cancer Research UK Beatson Institute, Switchback Road, Bearsden, Glasgow G61 1BD, UK; Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK. · Cancer Research UK Beatson Institute, Switchback Road, Bearsden, Glasgow G61 1BD, UK; Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK. Electronic address: j.morton@beatson.gla.ac.uk. · Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Cancer Division, Sydney, NSW 2010, Australia; St Vincent's Clinical School, Faculty of Medicine, University of NSW, Sydney, NSW 2010, Australia. Electronic address: p.timpson@garvan.org.au. ·Cell Rep · Pubmed #29898401.

ABSTRACT: Application of advanced intravital imaging facilitates dynamic monitoring of pathway activity upon therapeutic inhibition. Here, we assess resistance to therapeutic inhibition of the PI3K pathway within the hypoxic microenvironment of pancreatic ductal adenocarcinoma (PDAC) and identify a phenomenon whereby pronounced hypoxia-induced resistance is observed for three clinically relevant inhibitors. To address this clinical problem, we have mapped tumor hypoxia by both immunofluorescence and phosphorescence lifetime imaging of oxygen-sensitive nanoparticles and demonstrate that these hypoxic regions move transiently around the tumor. To overlay this microenvironmental information with drug response, we applied a FRET biosensor for Akt activity, which is a key effector of the PI3K pathway. Performing dual intravital imaging of drug response in different tumor compartments, we demonstrate an improved drug response to a combination therapy using the dual mTORC1/2 inhibitor AZD2014 with the hypoxia-activated pro-drug TH-302.

15 Article Rho Kinase Inhibition by AT13148 Blocks Pancreatic Ductal Adenocarcinoma Invasion and Tumor Growth. 2018

Rath, Nicola / Munro, June / Cutiongco, Marie Francene / Jagiełło, Alicja / Gadegaard, Nikolaj / McGarry, Lynn / Unbekandt, Mathieu / Michalopoulou, Evdokia / Kamphorst, Jurre J / Sumpton, David / Mackay, Gillian / Vennin, Claire / Pajic, Marina / Timpson, Paul / Olson, Michael F. ·Cancer Research UK Beatson Institute, Glasgow, United Kingdom. · Division of Biomedical Engineering, School of Engineering, University of Glasgow, Glasgow, United Kingdom. · Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom. · The Garvan Institute of Medical Research & The Kinghorn Cancer Centre, Sydney, Australia. · St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Kensington, Australia. · Cancer Research UK Beatson Institute, Glasgow, United Kingdom. m.olson@beatson.gla.ac.uk. ·Cancer Res · Pubmed #29669760.

ABSTRACT: The high mortality of pancreatic cancer demands that new therapeutic avenues be developed. The orally available small-molecule inhibitor AT13148 potently inhibits ROCK1 and ROCK2 kinases that regulate the actomyosin cytoskeleton. We previously reported that ROCK kinase expression increases with human and mouse pancreatic cancer progression and that conditional ROCK activation accelerates mortality in a genetically modified

16 Article Tailored first-line and second-line CDK4-targeting treatment combinations in mouse models of pancreatic cancer. 2018

Chou, Angela / Froio, Danielle / Nagrial, Adnan M / Parkin, Ashleigh / Murphy, Kendelle J / Chin, Venessa T / Wohl, Dalia / Steinmann, Angela / Stark, Rhys / Drury, Alison / Walters, Stacey N / Vennin, Claire / Burgess, Andrew / Pinese, Mark / Chantrill, Lorraine A / Cowley, Mark J / Molloy, Timothy J / Anonymous170925 / Waddell, Nicola / Johns, Amber / Grimmond, Sean M / Chang, David K / Biankin, Andrew V / Sansom, Owen J / Morton, Jennifer P / Grey, Shane T / Cox, Thomas R / Turchini, John / Samra, Jaswinder / Clarke, Stephen J / Timpson, Paul / Gill, Anthony J / Pajic, Marina. ·The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales, Australia. · Faculty of Medicine, St Vincent's Clinical School, University of NSW, Sydney, New South Wales, Australia. · Department of Anatomical Pathology, SYDPATH, Darlinghurst, Australia. · Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney, New South Wales, Australia. · St. Vincent's Hospital, Darlinghurst, Australia. · St Vincent's Centre for Applied Medical Research, Darlinghurst, New South Wales, Australia. · Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Queensland, Australia. · University of Melbourne, Melbourne, Victoria, Australia. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK. · West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK. · Department of Surgery, Cancer Research UK, Beatson Institute, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK. · Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia. · Department of Anatomical Pathology, Royal North Shore Hospital, Sydney, New South Wales, Australia. · Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, New South Wales, Australia. · Department of Surgery, Royal North Shore Hospital, Sydney, New South Wales, Australia. ·Gut · Pubmed #29080858.

ABSTRACT: OBJECTIVE: Extensive molecular heterogeneity of pancreatic ductal adenocarcinoma (PDA), few effective therapies and high mortality make this disease a prime model for advancing development of tailored therapies. The p16-cyclin D-cyclin-dependent kinase 4/6-retinoblastoma (RB) protein (CDK4) pathway, regulator of cell proliferation, is deregulated in PDA. Our aim was to develop a novel personalised treatment strategy for PDA based on targeting CDK4. DESIGN: Sensitivity to potent CDK4/6 inhibitor PD-0332991 (palbociclib) was correlated to protein and genomic data in 19 primary patient-derived PDA lines to identify biomarkers of response. In vivo efficacy of PD-0332991 and combination therapies was determined in subcutaneous, intrasplenic and orthotopic tumour models derived from genome-sequenced patient specimens and genetically engineered model. Mechanistically, monotherapy and combination therapy were investigated in the context of tumour cell and extracellular matrix (ECM) signalling. Prognostic relevance of companion biomarker, RB protein, was evaluated and validated in independent PDA patient cohorts (>500 specimens). RESULTS: Subtype-specific in vivo efficacy of PD-0332991-based therapy was for the first time observed at multiple stages of PDA progression: primary tumour growth, recurrence (second-line therapy) and metastatic setting and may potentially be guided by a simple biomarker (RB protein). PD-0332991 significantly disrupted surrounding ECM organisation, leading to increased quiescence, apoptosis, improved chemosensitivity, decreased invasion, metastatic spread and PDA progression in vivo. RB protein is prevalent in primary operable and metastatic PDA and may present a promising predictive biomarker to guide this therapeutic approach. CONCLUSION: This study demonstrates the promise of CDK4 inhibition in PDA over standard therapy when applied in a molecular subtype-specific context.

17 Article Effective modulation of stromal signaling through ROCK inhibition: Is it all in the timing? 2017

Chin, Venessa T / Vennin, Claire / Timpson, Paul / Pajic, Marina. ·The Kinghorn Cancer Centre, The Garvan Institute of Medical Research, Darlinghurst, Sydney, Australia. · St Vincent's Clinical School, Faculty of Medicine, University of NSW, Sydney, Australia. ·Mol Cell Oncol · Pubmed #29057302.

ABSTRACT: Our recent publication demonstrates that transient inhibition of Rho-associated kinase signaling within stroma, significantly decreased

18 Article A RhoA-FRET Biosensor Mouse for Intravital Imaging in Normal Tissue Homeostasis and Disease Contexts. 2017

Nobis, Max / Herrmann, David / Warren, Sean C / Kadir, Shereen / Leung, Wilfred / Killen, Monica / Magenau, Astrid / Stevenson, David / Lucas, Morghan C / Reischmann, Nadine / Vennin, Claire / Conway, James R W / Boulghourjian, Alice / Zaratzian, Anaiis / Law, Andrew M / Gallego-Ortega, David / Ormandy, Christopher J / Walters, Stacey N / Grey, Shane T / Bailey, Jacqueline / Chtanova, Tatyana / Quinn, Julian M W / Baldock, Paul A / Croucher, Peter I / Schwarz, Juliane P / Mrowinska, Agata / Zhang, Lei / Herzog, Herbert / Masedunskas, Andrius / Hardeman, Edna C / Gunning, Peter W / Del Monte-Nieto, Gonzalo / Harvey, Richard P / Samuel, Michael S / Pajic, Marina / McGhee, Ewan J / Johnsson, Anna-Karin E / Sansom, Owen J / Welch, Heidi C E / Morton, Jennifer P / Strathdee, Douglas / Anderson, Kurt I / Timpson, Paul. ·The Garvan Institute of Medical Research, St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW 2010, Australia. · Cancer Research UK Beatson Institute, Switchback Road, Bearsden, Glasgow G611BD, UK. · Neuromuscular and Regenerative Medicine Unit, University of New South Wales, Sydney, NSW 2010, Australia; Oncology Research Unit, School of Medical Sciences, University of New South Wales, Sydney, NSW 2010, Australia. · Neuromuscular and Regenerative Medicine Unit, University of New South Wales, Sydney, NSW 2010, Australia. · Oncology Research Unit, School of Medical Sciences, University of New South Wales, Sydney, NSW 2010, Australia. · Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research Institute, Sydney, NSW 2010, Australia; St. Vincent's Clinical School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia. · Centre for Cancer Biology, SA Pathology and University of South Australia School of Medicine, University of Adelaide, Adelaide, SA 5000, Australia. · Signalling Programme, Babraham Institute, Cambridge CB223AT, UK. · Francis Crick Institute, London NW11AT, UK. Electronic address: kurt.anderson@crick.ac.uk. · The Garvan Institute of Medical Research, St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW 2010, Australia. Electronic address: p.timpson@garvan.org.au. ·Cell Rep · Pubmed #28978480.

ABSTRACT: The small GTPase RhoA is involved in a variety of fundamental processes in normal tissue. Spatiotemporal control of RhoA is thought to govern mechanosensing, growth, and motility of cells, while its deregulation is associated with disease development. Here, we describe the generation of a RhoA-fluorescence resonance energy transfer (FRET) biosensor mouse and its utility for monitoring real-time activity of RhoA in a variety of native tissues in vivo. We assess changes in RhoA activity during mechanosensing of osteocytes within the bone and during neutrophil migration. We also demonstrate spatiotemporal order of RhoA activity within crypt cells of the small intestine and during different stages of mammary gestation. Subsequently, we reveal co-option of RhoA activity in both invasive breast and pancreatic cancers, and we assess drug targeting in these disease settings, illustrating the potential for utilizing this mouse to study RhoA activity in vivo in real time.

19 Article Lost in translation: returning germline genetic results in genome-scale cancer research. 2017

Johns, Amber L / McKay, Skye H / Humphris, Jeremy L / Pinese, Mark / Chantrill, Lorraine A / Mead, R Scott / Tucker, Katherine / Andrews, Lesley / Goodwin, Annabel / Leonard, Conrad / High, Hilda A / Nones, Katia / Patch, Ann-Marie / Merrett, Neil D / Pavlakis, Nick / Kassahn, Karin S / Samra, Jaswinder S / Miller, David K / Chang, David K / Pajic, Marina / Anonymous6590904 / Pearson, John V / Grimmond, Sean M / Waddell, Nicola / Zeps, Nikolajs / Gill, Anthony J / Biankin, Andrew V. ·Cancer Research Program, Garvan Institute of Medical Research, Kinghorn Cancer Centre, Sydney, Australia. · St Vincents Hospital, Darlinghurst, Australia. · Western Sydney University Clinical School, Sydney, Australia. · Genetics Department, SEALS Pathology, Prince of Wales Hospital, Randwick, Sydney, Australia. · School of Medicine, University of New South Wales, Sydney, Australia. · Hereditary Cancer Clinic, Prince of Wales Hospital, Randwick, Sydney, Australia. · Cancer Genetics Department, Royal Prince Alfred Hospital and Liverpool Hospital, Sydney, NSW, Australia. · QIMR Berghofer Medical Research Institute, Brisbane, Australia. · Sydney Cancer Genetics, Sydney, Australia. · Department of Surgery, Bankstown Hospital, Eldridge Road, Bankstown, Sydney, Australia. · Division of Surgery, School of Medicine, Western Sydney University, Sydney, Australia. · Department of Medical Oncology, Royal North Shore Hospital and Faculty of Medicine, University of Sydney, Sydney, Australia. · Genetic and Molecular Pathology, SA Pathology, Women's and Children's Hospital, North Adelaide, Adelaide, Australia. · Department of Surgery, Royal North Shore Hospital, Sydney, Australia. · Illumina Inc, 5200 Illumina Way, San Diego, CA, 92122, USA. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, UK. · West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK. · South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Liverpool, Australia. · University of Melbourne, Parkville, Australia. · St John of God Subiaco, Perth, Australia. · School of Surgery, The University of Western Australia, Perth, Australia. · Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney Australia and University of Sydney, Sydney, Australia. · Cancer Research Program, Garvan Institute of Medical Research, Kinghorn Cancer Centre, Sydney, Australia. andrew.biankin@glasgow.ac.uk. · West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK. andrew.biankin@glasgow.ac.uk. · South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Liverpool, Australia. andrew.biankin@glasgow.ac.uk. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow, UK. andrew.biankin@glasgow.ac.uk. ·Genome Med · Pubmed #28454591.

ABSTRACT: BACKGROUND: The return of research results (RoR) remains a complex and well-debated issue. Despite the debate, actual data related to the experience of giving individual results back, and the impact these results may have on clinical care and health outcomes, is sorely lacking. Through the work of the Australian Pancreatic Cancer Genome Initiative (APGI) we: (1) delineate the pathway back to the patient where actionable research data were identified; and (2) report the clinical utilisation of individual results returned. Using this experience, we discuss barriers and opportunities associated with a comprehensive process of RoR in large-scale genomic research that may be useful for others developing their own policies. METHODS: We performed whole-genome (n = 184) and exome (n = 208) sequencing of matched tumour-normal DNA pairs from 392 patients with sporadic pancreatic cancer (PC) as part of the APGI. We identified pathogenic germline mutations in candidate genes (n = 130) with established predisposition to PC or medium-high penetrance genes with well-defined cancer associated syndromes or phenotypes. Variants from candidate genes were annotated and classified according to international guidelines. Variants were considered actionable if clinical utility was established, with regard to prevention, diagnosis, prognostication and/or therapy. RESULTS: A total of 48,904 germline variants were identified, with 2356 unique variants undergoing annotation and in silico classification. Twenty cases were deemed actionable and were returned via previously described RoR framework, representing an actionable finding rate of 5.1%. Overall, 1.78% of our cohort experienced clinical benefit from RoR. CONCLUSION: Returning research results within the context of large-scale genomics research is a labour-intensive, highly variable, complex operation. Results that warrant action are not infrequent, but the prevalence of those who experience a clinical difference as a result of returning individual results is currently low.

20 Article Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy, and metastasis. 2017

Vennin, Claire / Chin, Venessa T / Warren, Sean C / Lucas, Morghan C / Herrmann, David / Magenau, Astrid / Melenec, Pauline / Walters, Stacey N / Del Monte-Nieto, Gonzalo / Conway, James R W / Nobis, Max / Allam, Amr H / McCloy, Rachael A / Currey, Nicola / Pinese, Mark / Boulghourjian, Alice / Zaratzian, Anaiis / Adam, Arne A S / Heu, Celine / Nagrial, Adnan M / Chou, Angela / Steinmann, Angela / Drury, Alison / Froio, Danielle / Giry-Laterriere, Marc / Harris, Nathanial L E / Phan, Tri / Jain, Rohit / Weninger, Wolfgang / McGhee, Ewan J / Whan, Renee / Johns, Amber L / Samra, Jaswinder S / Chantrill, Lorraine / Gill, Anthony J / Kohonen-Corish, Maija / Harvey, Richard P / Biankin, Andrew V / Anonymous10351124 / Evans, T R Jeffry / Anderson, Kurt I / Grey, Shane T / Ormandy, Christopher J / Gallego-Ortega, David / Wang, Yingxiao / Samuel, Michael S / Sansom, Owen J / Burgess, Andrew / Cox, Thomas R / Morton, Jennifer P / Pajic, Marina / Timpson, Paul. ·The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia. · St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia. · Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research Institute, Sydney, New South Wales 2010, Australia. · Biomedical Imaging Facility, Mark Wainwright Analytical Centre, Lowy Cancer Research Centre, University of New South Wales, Sydney, New South Wales 2052, Australia. · Department of Pathology, St. Vincent's Hospital, Sydney, New South Wales 2010, Australia. · Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, New South Wales 2522, Australia. · Immune Imaging Program, Centenary Institute, University of Sydney, Sydney, New South Wales 2006, Australia. · University of Sydney Medical School, Sydney, New South Wales 2006, Australia. · Department of Dermatology, Royal Prince Alfred Hospital, Camperdown, New South Wales 2050, Australia. · Cancer Research UK Beatson Institute, Glasgow, Scotland G61 BD, U.K. · Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research and Royal North Shore Hospital, Sydney, New South Wales 2065, Australia. · University of Sydney, Sydney, New South Wales 2006, Australia. · Australian Pancreatic Cancer Genome Initiative. · Department of Surgery, Royal North Shore Hospital, Sydney, New South Wales 2065, Australia. · Macarthur Cancer Therapy Centre, Campbelltown Hospital, Sydney, New South Wales 2560, Australia. · School of Medicine, Western Sydney University, Penrith, Sydney, New South Wales 2751, Australia. · School of Biotechnology and Biomolecular Science, University of New South Wales, Sydney, New South Wales 2052, Australia. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Scotland G61 BD, U.K. · West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Scotland G61 BD, U.K. · Department of Bioengineering, Institute of Engineering in Medicine, University of California, San Diego, San Diego, CA 92121, USA. · Centre for Cancer Biology, SA Pathology and University of South Australia School of Medicine, University of Adelaide, Adelaide, South Australia 5000, Australia. · The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia. m.pajic@garvan.org.au p.timpson@garvan.org.au. ·Sci Transl Med · Pubmed #28381539.

ABSTRACT: The emerging standard of care for patients with inoperable pancreatic cancer is a combination of cytotoxic drugs gemcitabine and Abraxane, but patient response remains moderate. Pancreatic cancer development and metastasis occur in complex settings, with reciprocal feedback from microenvironmental cues influencing both disease progression and drug response. Little is known about how sequential dual targeting of tumor tissue tension and vasculature before chemotherapy can affect tumor response. We used intravital imaging to assess how transient manipulation of the tumor tissue, or "priming," using the pharmaceutical Rho kinase inhibitor Fasudil affects response to chemotherapy. Intravital Förster resonance energy transfer imaging of a cyclin-dependent kinase 1 biosensor to monitor the efficacy of cytotoxic drugs revealed that priming improves pancreatic cancer response to gemcitabine/Abraxane at both primary and secondary sites. Transient priming also sensitized cells to shear stress and impaired colonization efficiency and fibrotic niche remodeling within the liver, three important features of cancer spread. Last, we demonstrate a graded response to priming in stratified patient-derived tumors, indicating that fine-tuned tissue manipulation before chemotherapy may offer opportunities in both primary and metastatic targeting of pancreatic cancer.

21 Article SerpinB2 regulates stromal remodelling and local invasion in pancreatic cancer. 2017

Harris, N L E / Vennin, C / Conway, J R W / Vine, K L / Pinese, M / Cowley, M J / Shearer, R F / Lucas, M C / Herrmann, D / Allam, A H / Pajic, M / Morton, J P / Anonymous2000901 / Biankin, A V / Ranson, M / Timpson, P / Saunders, D N. ·Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, Australia. · Centre for Medical and Molecular Bioscience, University of Wollongong, Wollongong, Australia. · School of Biological Sciences, University of Wollongong, Wollongong, Australia. · Kinghorn Cancer Center, Garvan Institute of Medical Research, Darlinghurst, Australia. · St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Darlinghurst, Australia. · Cancer Research UK Beatson Institute, Glasgow, Scotland. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK. · School of Medical Sciences, University of New South Wales, Sydney, Australia. ·Oncogene · Pubmed #28346421.

ABSTRACT: Pancreatic cancer has a devastating prognosis, with an overall 5-year survival rate of ~8%, restricted treatment options and characteristic molecular heterogeneity. SerpinB2 expression, particularly in the stromal compartment, is associated with reduced metastasis and prolonged survival in pancreatic ductal adenocarcinoma (PDAC) and our genomic analysis revealed that SERPINB2 is frequently deleted in PDAC. We show that SerpinB2 is required by stromal cells for normal collagen remodelling in vitro, regulating fibroblast interaction and engagement with collagen in the contracting matrix. In a pancreatic cancer allograft model, co-injection of PDAC cancer cells and SerpinB2

22 Article Whole-genome landscape of pancreatic neuroendocrine tumours. 2017

Scarpa, Aldo / Chang, David K / Nones, Katia / Corbo, Vincenzo / Patch, Ann-Marie / Bailey, Peter / Lawlor, Rita T / Johns, Amber L / Miller, David K / Mafficini, Andrea / Rusev, Borislav / Scardoni, Maria / Antonello, Davide / Barbi, Stefano / Sikora, Katarzyna O / Cingarlini, Sara / Vicentini, Caterina / McKay, Skye / Quinn, Michael C J / Bruxner, Timothy J C / Christ, Angelika N / Harliwong, Ivon / Idrisoglu, Senel / McLean, Suzanne / Nourse, Craig / Nourbakhsh, Ehsan / Wilson, Peter J / Anderson, Matthew J / Fink, J Lynn / Newell, Felicity / Waddell, Nick / Holmes, Oliver / Kazakoff, Stephen H / Leonard, Conrad / Wood, Scott / Xu, Qinying / Nagaraj, Shivashankar Hiriyur / Amato, Eliana / Dalai, Irene / Bersani, Samantha / Cataldo, Ivana / Dei Tos, Angelo P / Capelli, Paola / Davì, Maria Vittoria / Landoni, Luca / Malpaga, Anna / Miotto, Marco / Whitehall, Vicki L J / Leggett, Barbara A / Harris, Janelle L / Harris, Jonathan / Jones, Marc D / Humphris, Jeremy / Chantrill, Lorraine A / Chin, Venessa / Nagrial, Adnan M / Pajic, Marina / Scarlett, Christopher J / Pinho, Andreia / Rooman, Ilse / Toon, Christopher / Wu, Jianmin / Pinese, Mark / Cowley, Mark / Barbour, Andrew / Mawson, Amanda / Humphrey, Emily S / Colvin, Emily K / Chou, Angela / Lovell, Jessica A / Jamieson, Nigel B / Duthie, Fraser / Gingras, Marie-Claude / Fisher, William E / Dagg, Rebecca A / Lau, Loretta M S / Lee, Michael / Pickett, Hilda A / Reddel, Roger R / Samra, Jaswinder S / Kench, James G / Merrett, Neil D / Epari, Krishna / Nguyen, Nam Q / Zeps, Nikolajs / Falconi, Massimo / Simbolo, Michele / Butturini, Giovanni / Van Buren, George / Partelli, Stefano / Fassan, Matteo / Anonymous6880896 / Khanna, Kum Kum / Gill, Anthony J / Wheeler, David A / Gibbs, Richard A / Musgrove, Elizabeth A / Bassi, Claudio / Tortora, Giampaolo / Pederzoli, Paolo / Pearson, John V / Waddell, Nicola / Biankin, Andrew V / Grimmond, Sean M. ·ARC-Net Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona 37134, Italy. · Department of Pathology and Diagnostics, University and Hospital Trust of Verona, Verona 37134, Italy. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1QH, UK. · West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow G31 2ER, UK. · The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia. · Department of Surgery, Bankstown Hospital, Eldridge Road, Bankstown, Sydney, New South Wales 2200, Australia. · South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Liverpool, New South Wales 2170, Australia. · QIMR Berghofer Medical Research Institute, Herston Road, Brisbane 4006, Australia. · Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia. · Department of Surgery, Pancreas Institute, University and Hospital Trust of Verona, Verona 37134, Italy. · Medical Oncology, University and Hospital Trust of Verona, Verona, Italy. · Department of Pathology, General Hospital of Treviso, Department of Medicine, University of Padua, Italy. · Department of Medicine, Section of Endocrinology, University and Hospital Trust of Verona, Verona, Italy. · The University of Queensland, School of Medicine, Brisbane 4006, Australia. · Pathology Queensland, Brisbane 4006, Australia. · Royal Brisbane and Women's Hospital, Department of Gastroenterology and Hepatology, Brisbane 4006, Australia. · Institute of Health Biomedical Innovation, Queensland University of Technology, Brisbane, Australia. · School of Environmental &Life Sciences, University of Newcastle, Ourimbah, New South Wales 2258, Australia. · Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Centre for Cancer Bioinformatics, Peking University Cancer Hospital &Institute, Beijing 100142, China. · Department of Surgery, Princess Alexandra Hospital, Ipswich Rd, Woollongabba, Queensland 4102, Australia. · Department of Anatomical Pathology. St Vincent's Hospital, Sydney, New South Wales 2010, Australia. · Academic Unit of Surgery, School of Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow Royal Infirmary, Glasgow G4 OSF, UK. · Department of Pathology, Queen Elizabeth University Hospital, Greater Glasgow &Clyde NHS, Glasgow G51 4TF, UK. · Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza, MS226, Houston, Texas 77030-3411, USA. · Michael E. DeBakey Department of Surgery and The Elkins Pancreas Center, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030-3411, USA. · Children's Hospital at Westmead, Westmead, New South Wales 2145, Australia. · Children's Medical Research Institute, The University of Sydney, Westmead, New South Wales 2145, Australia. · Department of Surgery, Royal North Shore Hospital, St Leonards, Sydney, New South Wales 2065, Australia. · University of Sydney. Sydney, New South Wales 2006, Australia. · Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, New South Wales 2050, Australia. · School of Medicine, Western Sydney University, Penrith, New South Wales 2175, Australia. · Department of Surgery, Fremantle Hospital, Alma Street, Fremantle, Western Australia 6160, Australia. · Department of Gastroenterology, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia 5000, Australia. · School of Surgery M507, University of Western Australia, 35 Stirling Highway, Nedlands, Western Australia 6009, Australia. · St John of God Pathology, 12 Salvado Rd, Subiaco, Western Australia 6008, Australia. · Bendat Family Comprehensive Cancer Centre, St John of God Subiaco Hospital, Subiaco, Western Australia 6008, Australia. · University of Melbourne Centre for Cancer Research, University of Melbourne, Melbourne, 3010, Victoria, Australia. ·Nature · Pubmed #28199314.

ABSTRACT: The diagnosis of pancreatic neuroendocrine tumours (PanNETs) is increasing owing to more sensitive detection methods, and this increase is creating challenges for clinical management. We performed whole-genome sequencing of 102 primary PanNETs and defined the genomic events that characterize their pathogenesis. Here we describe the mutational signatures they harbour, including a deficiency in G:C > T:A base excision repair due to inactivation of MUTYH, which encodes a DNA glycosylase. Clinically sporadic PanNETs contain a larger-than-expected proportion of germline mutations, including previously unreported mutations in the DNA repair genes MUTYH, CHEK2 and BRCA2. Together with mutations in MEN1 and VHL, these mutations occur in 17% of patients. Somatic mutations, including point mutations and gene fusions, were commonly found in genes involved in four main pathways: chromatin remodelling, DNA damage repair, activation of mTOR signalling (including previously undescribed EWSR1 gene fusions), and telomere maintenance. In addition, our gene expression analyses identified a subgroup of tumours associated with hypoxia and HIF signalling.

23 Article Hypermutation In Pancreatic Cancer. 2017

Humphris, Jeremy L / Patch, Ann-Marie / Nones, Katia / Bailey, Peter J / Johns, Amber L / McKay, Skye / Chang, David K / Miller, David K / Pajic, Marina / Kassahn, Karin S / Quinn, Michael C J / Bruxner, Timothy J C / Christ, Angelika N / Harliwong, Ivon / Idrisoglu, Senel / Manning, Suzanne / Nourse, Craig / Nourbakhsh, Ehsan / Stone, Andrew / Wilson, Peter J / Anderson, Matthew / Fink, J Lynn / Holmes, Oliver / Kazakoff, Stephen / Leonard, Conrad / Newell, Felicity / Waddell, Nick / Wood, Scott / Mead, Ronald S / Xu, Qinying / Wu, Jianmin / Pinese, Mark / Cowley, Mark J / Jones, Marc D / Nagrial, Adnan M / Chin, Venessa T / Chantrill, Lorraine A / Mawson, Amanda / Chou, Angela / Scarlett, Christopher J / Pinho, Andreia V / Rooman, Ilse / Giry-Laterriere, Marc / Samra, Jaswinder S / Kench, James G / Merrett, Neil D / Toon, Christopher W / Epari, Krishna / Nguyen, Nam Q / Barbour, Andrew / Zeps, Nikolajs / Jamieson, Nigel B / McKay, Colin J / Carter, C Ross / Dickson, Euan J / Graham, Janet S / Duthie, Fraser / Oien, Karin / Hair, Jane / Morton, Jennifer P / Sansom, Owen J / Grützmann, Robert / Hruban, Ralph H / Maitra, Anirban / Iacobuzio-Donahue, Christine A / Schulick, Richard D / Wolfgang, Christopher L / Morgan, Richard A / Lawlor, Rita T / Rusev, Borislav / Corbo, Vincenzo / Salvia, Roberto / Cataldo, Ivana / Tortora, Giampaolo / Tempero, Margaret A / Anonymous871133 / Hofmann, Oliver / Eshleman, James R / Pilarsky, Christian / Scarpa, Aldo / Musgrove, Elizabeth A / Gill, Anthony J / Pearson, John V / Grimmond, Sean M / Waddell, Nicola / Biankin, Andrew V. ·The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia. · QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. · Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia; Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom; Department of Surgery, Bankstown Hospital, Bankstown, Sydney, New South Wales, Australia; South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales Australia, Liverpool, New South Wales, Australia; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom. · The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. · The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; St Vincent's Clinical School, Faculty of Medicine, University of New South Wales Australia, Darlinghurst, New South Wales, Australia. · Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia; Genetic and Molecular Pathology, Adelaide, South Australia, Australia; School of Biological Sciences, The University of Adelaide, Adelaide, South Australia, Australia. · Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. · Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia; St Vincent's Clinical School, Faculty of Medicine, University of New South Wales Australia, Darlinghurst, New South Wales, Australia. · The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; South Eastern Area Laboratory Services Pathology, Prince of Wales Hospital, Randwick, New South Wales, Australia; Sonic Genetics, Douglass Hanly Moir Pathology, New South Wales, Australia. · The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom. · The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; Macarthur Cancer Therapy Centre, Campbelltown Hospital, New South Wales, Australia. · The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; Department of Anatomical Pathology, SydPath, St Vincent's Hospital, New South Wales, Australia. · The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; School of Environmental and Life Sciences, University of Newcastle, Ourimbah, New South Wales, Australia. · Department of Surgery, Royal North Shore Hospital, Sydney, New South Wales, Australia; University of Sydney, Sydney, New South Wales, Australia. · The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; University of Sydney, Sydney, New South Wales, Australia; Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia. · Department of Surgery, Bankstown Hospital, Bankstown, Sydney, New South Wales, Australia; School of Medicine, Western Sydney University, Penrith, New South Wales, Australia. · Department of Surgery, Fiona Stanley Hospital, Murdoch, Washington. · Department of Gastroenterology, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia, Australia. · Department of Surgery, Princess Alexandra Hospital, Woollongabba, Queensland, Australia. · School of Surgery, University of Western Australia, Australia and St John of God Pathology, Subiaco, Washington. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom; Academic Unit of Surgery, School of Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow Royal Infirmary, Glasgow, United Kingdom. · West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom; Department of Medical Oncology, Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom. · Department of Pathology, Southern General Hospital, Greater Glasgow & Clyde National Health Service, Glasgow, United Kingdom. · Greater Glasgow and Clyde Bio-repository, Pathology Department, Queen Elizabeth University Hospital, Glasgow, United Kingdom. · Cancer Research UK Beatson Institute, Glasgow, United Kingdom; Institute for Cancer Science, University of Glasgow, Glasgow, United Kingdom. · Universitätsklinikum Erlangen, Erlangen, Germany. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine, Baltimore, Maryland. · ARC-NET Center for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy; Department of Pathology and Diagnostics, University of Verona, Verona, Italy. · Department of Medicine, University and Hospital Trust of Verona, Verona, Italy. · Division of Hematology and Oncology, University of California, San Francisco, California. · Australian Pancreatic Cancer Genome Initiative. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom. · Universitätsklinikum Erlangen, Department of Surgery, University of Erlangen-Nueremberg, Germany. · The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom; St Vincent's Clinical School, Faculty of Medicine, University of New South Wales Australia, Darlinghurst, New South Wales, Australia. · The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; University of Sydney, Sydney, New South Wales, Australia; Department of Anatomical Pathology, Royal North Shore Hospital, Sydney, New South Wales, Australia. · Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia; University of Melbourne Centre for Cancer Research, The University of Melbourne, Melbourne, Victoria, Australia. · QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. Electronic address: nic.waddell@qimrberghofer.edu.au. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom; Department of Surgery, Bankstown Hospital, Bankstown, Sydney, New South Wales, Australia; South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales Australia, Liverpool, New South Wales, Australia; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom. Electronic address: andrew.biankin@glasgow.ac.uk. ·Gastroenterology · Pubmed #27856273.

ABSTRACT: Pancreatic cancer is molecularly diverse, with few effective therapies. Increased mutation burden and defective DNA repair are associated with response to immune checkpoint inhibitors in several other cancer types. We interrogated 385 pancreatic cancer genomes to define hypermutation and its causes. Mutational signatures inferring defects in DNA repair were enriched in those with the highest mutation burdens. Mismatch repair deficiency was identified in 1% of tumors harboring different mechanisms of somatic inactivation of MLH1 and MSH2. Defining mutation load in individual pancreatic cancers and the optimal assay for patient selection may inform clinical trial design for immunotherapy in pancreatic cancer.

24 Article GATA6 regulates EMT and tumour dissemination, and is a marker of response to adjuvant chemotherapy in pancreatic cancer. 2017

Martinelli, Paola / Carrillo-de Santa Pau, Enrique / Cox, Trevor / Sainz, Bruno / Dusetti, Nelson / Greenhalf, William / Rinaldi, Lorenzo / Costello, Eithne / Ghaneh, Paula / Malats, Núria / Büchler, Markus / Pajic, Marina / Biankin, Andrew V / Iovanna, Juan / Neoptolemos, John / Real, Francisco X. ·Epithelial Carcinogenesis Group, Spanish National Cancer Research Center-CNIO, Madrid, Spain. · Cancer Progression and Metastasis Group, Institute for Cancer Research, Medical University Wien, Vienna, Austria. · Cancer Research UK Liverpool Clinical Trials Unit, University of Liverpool, Liverpool, UK. · NIHR Liverpool Pancreas Biomedical Research Unit, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK. · Department of Preventive Medicine, Public Health and Microbiology, Universidad Autónoma de Madrid, Madrid, Spain. · Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, France. · Institute for Research in Biomedicine (IRB), Barcelona, Spain. · Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Center-CNIO, Madrid, Spain. · Department for General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany. · Cancer Division, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, Australia. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK. · West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK. · South Western Sydney Clinical School, Faculty of Medicine, University of NSW, Liverpool, Australia. · Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain. ·Gut · Pubmed #27325420.

ABSTRACT: BACKGROUND AND AIMS: The role of GATA factors in cancer has gained increasing attention recently, but the function of GATA6 in pancreatic ductal adenocarcinoma (PDAC) is controversial. GATA6 is amplified in a subset of tumours and was proposed to be oncogenic, but high GATA6 levels are found in well-differentiated tumours and are associated with better patient outcome. By contrast, a tumour-suppressive function of GATA6 was demonstrated using genetic mouse models. We aimed at clarifying GATA6 function in PDAC. DESIGN: We combined GATA6 silencing and overexpression in PDAC cell lines with GATA6 ChIP-Seq and RNA-Seq data, in order to understand the mechanism of GATA6 functions. We then confirmed some of our observations in primary patient samples, some of which were included in the ESPAC-3 randomised clinical trial for adjuvant therapy. RESULTS: GATA6 inhibits the epithelial-mesenchymal transition (EMT) in vitro and cell dissemination in vivo. GATA6 has a unique proepithelial and antimesenchymal function, and its transcriptional regulation is direct and implies, indirectly, the regulation of other transcription factors involved in EMT. GATA6 is lost in tumours, in association with altered differentiation and the acquisition of a basal-like molecular phenotype, consistent with an epithelial-to-epithelial (ET CONCLUSIONS: We provide mechanistic insight into GATA6 tumour-suppressive function, its role as a regulator of canonical epithelial differentiation, and propose that loss of GATA6 expression is both prognostic and predictive of response to adjuvant therapy.

25 Article Resolution of Novel Pancreatic Ductal Adenocarcinoma Subtypes by Global Phosphotyrosine Profiling. 2016

Humphrey, Emily S / Su, Shih-Ping / Nagrial, Adnan M / Hochgräfe, Falko / Pajic, Marina / Lehrbach, Gillian M / Parton, Robert G / Yap, Alpha S / Horvath, Lisa G / Chang, David K / Biankin, Andrew V / Wu, Jianmin / Daly, Roger J. ·From the ‡Cancer Division and Kinghorn Cancer Centre, Garvan Institute of Medical Research, 384 Victoria St, Sydney, NSW 2010, Australia; §St Vincent's Hospital Clinical School, Faculty of Medicine, University of New South Wales, NSW 2052, Australia; · ¶Cancer Program, Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Level 1, Building 77, Monash University, VIC 3800, Australia; · ‖Competence Center Functional Genomics, University of Greifswald, F.-L-Jahnstr. 15, 17489 Greifswald, Germany; · From the ‡Cancer Division and Kinghorn Cancer Centre, Garvan Institute of Medical Research, 384 Victoria St, Sydney, NSW 2010, Australia; · **Division of Cell Biology and Molecular Medicine, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Brisbane QLD 4072, Australia; · From the ‡Cancer Division and Kinghorn Cancer Centre, Garvan Institute of Medical Research, 384 Victoria St, Sydney, NSW 2010, Australia; ‡‡Chris O'Brien Lifehouse, Missenden Road, Camperdown, NSW 2050, Australia; · §§Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK; · §§Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK; andrew.biankin@glasgow.ac.uk. · ¶¶Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Center for Cancer Bioinformatics, Peking University Cancer Hospital & Institute, 52 Fu-Cheng Road, Hai-Dian District, Beijing 100142, China From the ‡Cancer Division and Kinghorn Cancer Centre, Garvan Institute of Medical Research, 384 Victoria St, Sydney, NSW 2010, Australia; §St Vincent's Hospital Clinical School, Faculty of Medicine, University of New South Wales, NSW 2052, Australia; roger.daly@monash.edu wujm@bjmu.edu.cn. · ¶Cancer Program, Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Level 1, Building 77, Monash University, VIC 3800, Australia; roger.daly@monash.edu wujm@bjmu.edu.cn. ·Mol Cell Proteomics · Pubmed #27259358.

ABSTRACT: Comprehensive characterization of signaling in pancreatic ductal adenocarcinoma (PDAC) promises to enhance our understanding of the molecular aberrations driving this devastating disease, and may identify novel therapeutic targets as well as biomarkers that enable stratification of patients for optimal therapy. Here, we use immunoaffinity-coupled high-resolution mass spectrometry to characterize global tyrosine phosphorylation patterns across two large panels of human PDAC cell lines: the ATCC series (19 cell lines) and TKCC series (17 cell lines). This resulted in the identification and quantification of over 1800 class 1 tyrosine phosphorylation sites and the consistent segregation of both PDAC cell line series into three subtypes with distinct tyrosine phosphorylation profiles. Subtype-selective signaling networks were characterized by identification of subtype-enriched phosphosites together with pathway and network analyses. This revealed that the three subtypes characteristic of the ATCC series were associated with perturbations in signaling networks associated with cell-cell adhesion and epithelial-mesenchyme transition, mRNA metabolism, and receptor tyrosine kinase (RTK) signaling, respectively. Specifically, the third subtype exhibited enhanced tyrosine phosphorylation of multiple RTKs including the EGFR, ERBB3 and MET. Interestingly, a similar RTK-enriched subtype was identified in the TKCC series, and 'classifier' sites for each series identified using Random Forest models were able to predict the subtypes of the alternate series with high accuracy, highlighting the conservation of the three subtypes across the two series. Finally, RTK-enriched cell lines from both series exhibited enhanced sensitivity to the small molecule EGFR inhibitor erlotinib, indicating that their phosphosignature may provide a predictive biomarker for response to this targeted therapy. These studies highlight how resolution of subtype-selective signaling networks can provide a novel taxonomy for particular cancers, and provide insights into PDAC biology that can be exploited for improved patient management.

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