Pick Topic
Review Topic
List Experts
Examine Expert
Save Expert
  Site Guide ··   
Pancreatic Neoplasms: HELP
Articles by Michael A. Hollingsworth
Based on 51 articles published since 2009
(Why 51 articles?)
||||

Between 2009 and 2019, M. A. Hollingsworth wrote the following 51 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3
1 Review Emerging roles of the CXCL12/CXCR4 axis in pancreatic cancer progression and therapy. 2017

Sleightholm, Richard L / Neilsen, Beth K / Li, Jing / Steele, Maria M / Singh, Rakesh K / Hollingsworth, Michael A / Oupicky, David. ·Department of Pharmaceutical Sciences, University of Nebraska Medical Center, 985830 Nebraska Medical Center, Omaha, NE, USA. · Eppley Institute, University of Nebraska Medical Center, 985950 Nebraska Medical Center, Omaha, NE, USA. · Department of Pathology and Microbiology, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE, USA. · Eppley Institute, University of Nebraska Medical Center, 985950 Nebraska Medical Center, Omaha, NE, USA; Department of Pathology and Microbiology, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE, USA; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE, USA. · Department of Pharmaceutical Sciences, University of Nebraska Medical Center, 985830 Nebraska Medical Center, Omaha, NE, USA. Electronic address: david.oupicky@unmc.edu. ·Pharmacol Ther · Pubmed #28549596.

ABSTRACT: Chemokine networks regulate a variety of cellular, physiological, and immune processes. These normal functions can become appropriated by cancer cells to facilitate a more hospitable niche for aberrant cells by enhancing growth, proliferation, and metastasis. This is especially true in pancreatic cancer, where chemokine signaling is a vital component in the development of the supportive tumor microenvironment and the signaling between the cancer cells and surrounding stromal cells. Although expression patterns vary among cancer types, the chemokine receptor CXCR4 has been implicated in nearly every major malignancy and plays a prominent role in pancreatic cancer development and progression. This receptor, in conjunction with its primary chemokine ligand CXCL12, promotes pancreatic cancer development, invasion, and metastasis through the management of the tumor microenvironment via complex crosstalk with other pathways. Thus, CXCR4 likely contributes to the poor prognoses observed in patients afflicted with this malignancy. Recent exploration of combination therapies with CXCR4 antagonists have demonstrated improved outcomes, and abolishing the contribution of this pathway may prove crucial to effectively treat pancreatic cancer at both the primary tumor and metastases.

2 Review The lymphatic system and pancreatic cancer. 2016

Fink, Darci M / Steele, Maria M / Hollingsworth, Michael A. ·Eppley Institute, University of Nebraska Medical Center, Omaha, NE 68198-5950, USA. · Eppley Institute, University of Nebraska Medical Center, Omaha, NE 68198-5950, USA. Electronic address: mahollin@unmc.edu. ·Cancer Lett · Pubmed #26742462.

ABSTRACT: This review summarizes current knowledge of the biology, pathology and clinical understanding of lymphatic invasion and metastasis in pancreatic cancer. We discuss the clinical and biological consequences of lymphatic invasion and metastasis, including paraneoplastic effects on immune responses and consider the possible benefit of therapies to treat tumors that are localized to lymphatics. A review of current techniques and methods to study interactions between tumors and lymphatics is presented.

3 Review Early detection of sporadic pancreatic cancer: summative review. 2015

Chari, Suresh T / Kelly, Kimberly / Hollingsworth, Michael A / Thayer, Sarah P / Ahlquist, David A / Andersen, Dana K / Batra, Surinder K / Brentnall, Teresa A / Canto, Marcia / Cleeter, Deborah F / Firpo, Matthew A / Gambhir, Sanjiv Sam / Go, Vay Liang W / Hines, O Joe / Kenner, Barbara J / Klimstra, David S / Lerch, Markus M / Levy, Michael J / Maitra, Anirban / Mulvihill, Sean J / Petersen, Gloria M / Rhim, Andrew D / Simeone, Diane M / Srivastava, Sudhir / Tanaka, Masao / Vinik, Aaron I / Wong, David. ·From the *Department of Medicine, Mayo Clinic, Rochester, MN; †Department of Biomedical Engineering, University of Virginia, Charlottesville, VA; Departments of ‡Biochemistry and Molecular Biology, §Pathology and Microbiology, and ∥Surgery, Fred & Pamela Buffett Cancer Center, University of Nebraska, Omaha, NE; ¶Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Bethesda, MD; #Division of Gastroenterology, University of Washington, Seattle, WA; **Division of Gastroenterology, Johns Hopkins University School of Medicine, Baltimore, MD; ††Sawgrass Leadership Institute, Ponte Vedra Beach, FL; ‡‡Department of Surgery, University of Utah, Salt Lake City, UT; §§Department of Radiology, Stanford University School of Medicine, Stanford; ∥∥Department of Medicine, David Geffen School of Medicine, and ¶¶General Surgery, University of California Los Angeles, Los Angeles, CA; ##Kenner Family Research Fund; ***Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY; †††Department of Internal Medicine, University of Greifswald, Greifswald, Germany; ‡‡‡Division of Pathology and Laboratory Medicine, University of Texas MD Anderson Cancer Center, Houston, TX; §§§Department of Health Sciences Research, Mayo Clinic, Rochester, MN; ∥∥∥Gastroenterology Division, Department of Internal Medicine and Comprehensive Cancer Center, and ¶¶¶Department of Surgery, School of Medicine, University of Michigan, Ann Arbor, MI; ###Cancer Biomarkers Research Group, Division of Cancer Prevention, National Cancer Institute, Rockville, MD; ****Departments of Surgery and Oncology, Kyushu University, Fukuoka, Japan; ††††Department of Medicine, Eastern Virginia Medical School, Norfolk, VA; and ‡‡‡‡Division of Oral Biology and Medicine, CLA School of Dentistry, Jonnson Comprehensive Cancer Center, University of California Los Angeles, L ·Pancreas · Pubmed #25931254.

ABSTRACT: Pancreatic cancer (PC) is estimated to become the second leading cause of cancer death in the United States by 2020. Early detection is the key to improving survival in PC. Addressing this urgent need, the Kenner Family Research Fund conducted the inaugural Early Detection of Sporadic Pancreatic Cancer Summit Conference in 2014 in conjunction with the 45th Anniversary Meeting of the American Pancreatic Association and Japan Pancreas Society. This seminal convening of international representatives from science, practice, and clinical research was designed to facilitate challenging interdisciplinary conversations to generate innovative ideas leading to the creation of a defined collaborative strategic pathway for the future of the field. An in-depth summary of current efforts in the field, analysis of gaps in specific areas of expertise, and challenges that exist in early detection is presented within distinct areas of inquiry: Case for Early Detection: Definitions, Detection, Survival, and Challenges; Biomarkers for Early Detection; Imaging; and Collaborative Studies. In addition, an overview of efforts in familial PC is presented in an addendum to this article. It is clear from the summit deliberations that only strategically designed collaboration among investigators, institutions, and funders will lead to significant progress in early detection of sporadic PC.

4 Review Molecular pathology of early pancreatic cancer. 2010

Remmers, Neeley / Bailey, Jennifer M / Mohr, Ashley M / Hollingsworth, Michael A. ·Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA. ·Cancer Biomark · Pubmed #22112488.

ABSTRACT: We describe the pathology of early pancreatic cancer and present an overview of known molecular alterations that occur in these lesions. There are three defined precursor lesions in current models of pancreatic cancer: pancreatic intraepithelial neoplasia (PanIN), mucinous cystic neoplasms (MCN), and intraductal papillary mucinous neoplasms (IPMN). Molecular alterations detected in these lesions include: telomeres, K-ras and downstream targets, p16/CDKN2A, p53, SMAD4/DPC4, microRNAs, mucins and their post-translational processing, inflammatory cytokines, CEACAM, and epigenetic alterations. We summarize previous analyses of these markers as diagnostic markers of disease, and suggest areas of future study.

5 Article Indocyanine green loaded hyaluronan-derived nanoparticles for fluorescence-enhanced surgical imaging of pancreatic cancer. 2018

Qi, Bowen / Crawford, Ayrianne J / Wojtynek, Nicholas E / Holmes, Megan B / Souchek, Joshua J / Almeida-Porada, Graca / Ly, Quan P / Cohen, Samuel M / Hollingsworth, Michael A / Mohs, Aaron M. ·Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE. · Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE. · Wake Forest Institute for Regenerative Medicine, Wake Forest University Health Sciences, Winston-Salem, NC. · Department of Surgery, University of Nebraska Medical Center, Omaha, NE; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE. · Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE; Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE; Havlik-Wall Professor of Oncology, University of Nebraska Medical Center, Omaha, NE. · Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE. · Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE. Electronic address: aaron.mohs@unmc.edu. ·Nanomedicine · Pubmed #29325740.

ABSTRACT: Pancreatic ductal adenocarcinoma is highly lethal and surgical resection is the only potential curative treatment for the disease. In this study, hyaluronic acid derived nanoparticles with physico-chemically entrapped indocyanine green, termed NanoICG, were utilized for intraoperative near infrared fluorescence detection of pancreatic cancer. NanoICG was not cytotoxic to healthy pancreatic epithelial cells and did not induce chemotaxis or phagocytosis, it accumulated significantly within the pancreas in an orthotopic pancreatic ductal adenocarcinoma model, and demonstrated contrast-enhancement for pancreatic lesions relative to non-diseased portions of the pancreas. Fluorescence microscopy showed higher fluorescence intensity in pancreatic lesions and splenic metastases due to NanoICG compared to ICG alone. The in vivo safety profile of NanoICG, including, biochemical, hematological, and pathological analysis of NanoICG-treated healthy mice, indicates negligible toxicity. These results suggest that NanoICG is a promising contrast agent for intraoperative detection of pancreatic tumors.

6 Article Combination of mAb-AR20.5, anti-PD-L1 and PolyICLC inhibits tumor progression and prolongs survival of MUC1.Tg mice challenged with pancreatic tumors. 2018

Mehla, Kamiya / Tremayne, Jarrod / Grunkemeyer, James A / O'Connell, Kelly A / Steele, Maria M / Caffrey, Thomas C / Zhu, Xinyi / Yu, Fang / Singh, Pankaj K / Schultes, Birgit C / Madiyalakan, Ragupathy / Nicodemus, Christopher F / Hollingsworth, Michael A. ·The Eppley Institute for Cancer and Allied Diseases, University of Nebraska Medical Center, 986805 Nebraska Medical Center, Omaha, NE, 68198-6805, USA. · Mercaptor Discoveries Inc, Novato, CA, USA. · Shanghai Jiao Tong University School of Medicine, Lu Wan Qu, Shanghai Shi, China. · Department of Biostatistics, University of Nebraska Medical Center, Omaha, NE, USA. · Unum Therapeutics, Boston, MA, USA. · OncoQuest Inc., Edmonton, AB, Canada. · AIT Strategies, Franconia, NH, USA. · The Eppley Institute for Cancer and Allied Diseases, University of Nebraska Medical Center, 986805 Nebraska Medical Center, Omaha, NE, 68198-6805, USA. mahollin@unmc.edu. ·Cancer Immunol Immunother · Pubmed #29204701.

ABSTRACT: A substantial body of evidence suggests the existence of MUC1-specific antibodies and cytotoxic T cell activities in pancreatic cancer patients. However, tumor-induced immunosuppression renders these responses ineffective. The current study explores a novel therapeutic combination wherein tumor-bearing hosts can be immunologically primed with their own antigen, through opsonization with a tumor antigen-targeted antibody, mAb-AR20.5. We evaluated the efficacy of immunization with this antibody in combination with PolyICLC and anti-PD-L1. The therapeutic combination of mAb-AR20.5 + anti-PD-L1 + PolyICLC induced rejection of human MUC1 expressing tumors and provided a long-lasting, MUC1-specific cellular immune response, which could be adoptively transferred and shown to provide protection against tumor challenge in human MUC1 transgenic (MUC.Tg) mice. Furthermore, antibody depletion studies revealed that CD8 cells were effectors for the MUC1-specific immune response generated by the mAb-AR20.5 + anti-PD-L1 + PolyICLC combination. Multichromatic flow cytometry data analysis demonstrated a significant increase over time in circulating, activated CD8 T cells, CD3

7 Article Enhancer Reprogramming Promotes Pancreatic Cancer Metastasis. 2017

Roe, Jae-Seok / Hwang, Chang-Il / Somerville, Tim D D / Milazzo, Joseph P / Lee, Eun Jung / Da Silva, Brandon / Maiorino, Laura / Tiriac, Hervé / Young, C Megan / Miyabayashi, Koji / Filippini, Dea / Creighton, Brianna / Burkhart, Richard A / Buscaglia, Jonathan M / Kim, Edward J / Grem, Jean L / Lazenby, Audrey J / Grunkemeyer, James A / Hollingsworth, Michael A / Grandgenett, Paul M / Egeblad, Mikala / Park, Youngkyu / Tuveson, David A / Vakoc, Christopher R. ·Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA. · Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY 11724, USA. · Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Johns Hopkins Hospital, Baltimore, MD 21287, USA. · Division of Gastroenterology & Hepatology, Stony Brook University School of Medicine, Stony Brook, NY 11790, USA. · Division of Hematology/Oncology, UC Davis Medical Center, Sacramento, CA 95817, USA. · Department of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA. · Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA. · Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA. · Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY 11724, USA. Electronic address: dtuveson@cshl.edu. · Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA. Electronic address: vakoc@cshl.edu. ·Cell · Pubmed #28757253.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal human malignancies, owing in part to its propensity for metastasis. Here, we used an organoid culture system to investigate how transcription and the enhancer landscape become altered during discrete stages of disease progression in a PDA mouse model. This approach revealed that the metastatic transition is accompanied by massive and recurrent alterations in enhancer activity. We implicate the pioneer factor FOXA1 as a driver of enhancer activation in this system, a mechanism that renders PDA cells more invasive and less anchorage-dependent for growth in vitro, as well as more metastatic in vivo. In this context, FOXA1-dependent enhancer reprogramming activates a transcriptional program of embryonic foregut endoderm. Collectively, our study implicates enhancer reprogramming, FOXA1 upregulation, and a retrograde developmental transition in PDA metastasis.

8 Article MUC1 and HIF-1alpha Signaling Crosstalk Induces Anabolic Glucose Metabolism to Impart Gemcitabine Resistance to Pancreatic Cancer. 2017

Shukla, Surendra K / Purohit, Vinee / Mehla, Kamiya / Gunda, Venugopal / Chaika, Nina V / Vernucci, Enza / King, Ryan J / Abrego, Jaime / Goode, Gennifer D / Dasgupta, Aneesha / Illies, Alysha L / Gebregiworgis, Teklab / Dai, Bingbing / Augustine, Jithesh J / Murthy, Divya / Attri, Kuldeep S / Mashadova, Oksana / Grandgenett, Paul M / Powers, Robert / Ly, Quan P / Lazenby, Audrey J / Grem, Jean L / Yu, Fang / Matés, José M / Asara, John M / Kim, Jung-Whan / Hankins, Jordan H / Weekes, Colin / Hollingsworth, Michael A / Serkova, Natalie J / Sasson, Aaron R / Fleming, Jason B / Oliveto, Jennifer M / Lyssiotis, Costas A / Cantley, Lewis C / Berim, Lyudmyla / Singh, Pankaj K. ·Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198-5950, USA. · Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198-5950, USA; Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA. · Department of Chemistry, University of Nebraska-Lincoln, Lincoln, NE 68588, USA. · Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA. · Department of Surgery, University of Nebraska Medical Center, Omaha, NE 68198, USA. · Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA. · Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA. · Department of Biostatistics, University of Nebraska Medical Center, Omaha, NE 68198, USA. · Department of Molecular Biology and Biochemistry, University of Málaga and IBIMA, 29071 Málaga, Spain. · Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. · Department of Biological Sciences, The University of Texas at Dallas, 800 West Campbell Road, Richardson, TX 75080, USA. · Department of Radiology, University of Nebraska Medical Center, Omaha, NE 68198, USA. · Division of Medical Oncology, University of Colorado School of Medicine, Aurora, CO 80045, USA. · Department of Anesthesiology, University of Colorado Denver, Aurora, CO 80045, USA. · Department of Surgery, Health Sciences Center T18-065, Stony Brook Medicine, Stony Brook, NY 11794, USA. · Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48103, USA. · Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198-5950, USA; Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA. Electronic address: pankaj.singh@unmc.edu. ·Cancer Cell · Pubmed #28697344.

ABSTRACT: Poor response to cancer therapy due to resistance remains a clinical challenge. The present study establishes a widely prevalent mechanism of resistance to gemcitabine in pancreatic cancer, whereby increased glycolytic flux leads to glucose addiction in cancer cells and a corresponding increase in pyrimidine biosynthesis to enhance the intrinsic levels of deoxycytidine triphosphate (dCTP). Increased levels of dCTP diminish the effective levels of gemcitabine through molecular competition. We also demonstrate that MUC1-regulated stabilization of hypoxia inducible factor-1α (HIF-1α) mediates such metabolic reprogramming. Targeting HIF-1α or de novo pyrimidine biosynthesis, in combination with gemcitabine, strongly diminishes tumor burden. Finally, reduced expression of TKT and CTPS, which regulate flux into pyrimidine biosynthesis, correlates with better prognosis in pancreatic cancer patients on fluoropyrimidine analogs.

9 Article A Combination of MUC5AC and CA19-9 Improves the Diagnosis of Pancreatic Cancer: A Multicenter Study. 2017

Kaur, Sukhwinder / Smith, Lynette M / Patel, Asish / Menning, Melanie / Watley, Duncan C / Malik, Saad S / Krishn, Shiv Ram / Mallya, Kavita / Aithal, Abhijit / Sasson, Aaron R / Johansson, Sonny L / Jain, Maneesh / Singh, Shailender / Guha, Sushovan / Are, Chandrakanth / Raimondo, Massimo / Hollingsworth, Michael A / Brand, Randall E / Batra, Surinder K. ·Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, USA. · Department of Biostatistics, University of Nebraska Medical Center, Omaha, Nebraska, USA. · Department of Surgery, University of Nebraska Medical Center, Omaha, Nebraska, USA. · Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska, USA. · Division of Gastroenterology, Hepatology, and Nutrition, The University of Texas Medical School and Health Science Center at Houston, Houston, Texas, USA. · Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, Florida, USA. · Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, USA. · University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA. · Fred and Pamela Buffett Cancer Center, Omaha, Nebraska, USA. ·Am J Gastroenterol · Pubmed #27845339.

ABSTRACT: OBJECTIVES: Pancreatic cancer (PC) is a lethal malignancy that lacks specific diagnostic markers. The present study explores the diagnostic potential of the most differentially overexpressed secretory mucin MUC5AC alone and in combination with CA19-9 using multi-center training and validation sets. METHODS: The expression of MUC5AC in benign pancreatic pathologies, PC precursor lesions, primary PC tissues and metastatic lesions was evaluated by immunohistochemistry. Circulating MUC5AC levels were measured using sandwich ELISA assay developed in-house, and CA19-9 was measured using radioimmunoassay. A combined training set (n=346) was used to evaluate the diagnostic (n=241) and predictive (n=105, total samples 201 from pre- and post-surgical and chemotherapy set) significance of MUC5AC. Results were further validated with a pre-defined cut-off value using independent sets from the Mayo Clinic (n=94) and the University of Pittsburgh Medical Center (n=321). RESULTS: Tissue expression analyses indicated the de novo expression of MUC5AC in pancreatic intraepithelial precursor lesions 1A (PanIN1A); the expression was maintained through all stages of progression to invasive adenocarcinoma. The median circulating MUC5AC levels in patients with resectable early-stage PC (EPC) (stage 1/2; 67.2 ng/ml, IQR: 23.9-382.1) and unresectable late-stage PC (LPC) (stage 3/4; 389.7 ng/ml, IQR: 87.7-948.6) were significantly higher compared with (P-value ≤0.0001) benign controls (BC) (7.2 ng/ml, IQR: 0.4-26.5) and (P-value ≤0.0001) chronic pancreatitis (CP) controls (8.4 ng/ml, IQR: 1.5-19.2). In the diagnostic training set (n=241), MUC5AC efficiently differentiated EPC from healthy controls (HC) (83%/80% sensitive (SN)/specific (SP)), BC (67%/87% SN/SP), and CP (83%/77% SN/SP). Independent validation sets from the Mayo Clinic and UPMC confirmed the diagnostic potential of MUC5AC to differentiate EPC from BC (68%/73%; 65%/83%) and CP (68%/79%; 65%/72%). Furthermore, MUC5AC and CA19-9 combination significantly improved (p-value < 0.001) the diagnostic accuracy for differentiating resectable cases from controls. CONCLUSIONS: MUC5AC is a valuable diagnostic biomarker, either alone or in combination with CA19-9, to differentiate PC from CP and benign controls.

10 Article Association of Distinct Mutational Signatures With Correlates of Increased Immune Activity in Pancreatic Ductal Adenocarcinoma. 2017

Connor, Ashton A / Denroche, Robert E / Jang, Gun Ho / Timms, Lee / Kalimuthu, Sangeetha N / Selander, Iris / McPherson, Treasa / Wilson, Gavin W / Chan-Seng-Yue, Michelle A / Borozan, Ivan / Ferretti, Vincent / Grant, Robert C / Lungu, Ilinca M / Costello, Eithne / Greenhalf, William / Palmer, Daniel / Ghaneh, Paula / Neoptolemos, John P / Buchler, Markus / Petersen, Gloria / Thayer, Sarah / Hollingsworth, Michael A / Sherker, Alana / Durocher, Daniel / Dhani, Neesha / Hedley, David / Serra, Stefano / Pollett, Aaron / Roehrl, Michael H A / Bavi, Prashant / Bartlett, John M S / Cleary, Sean / Wilson, Julie M / Alexandrov, Ludmil B / Moore, Malcolm / Wouters, Bradly G / McPherson, John D / Notta, Faiyaz / Stein, Lincoln D / Gallinger, Steven. ·PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada2Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada3Hepatobiliary/Pancreatic Surgical Oncology Program, University Health Network, Toronto, Ontario, Canada. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada4Informatics and Bio-computing Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada4Informatics and Bio-computing Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada5Department of Statistical Science, University of Toronto, Toronto, Ontario, Canada. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada6Genome Technologies Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada. · Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. · Informatics and Bio-computing Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada2Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. · Transformative Pathology, Ontario Institute for Cancer Research, Toronto, Ontario, Canada. · University of Liverpool, Liverpool, England. · Heidelberg University Hospital, Heidelberg, Germany. · Mayo Clinic, Rochester, Minnesota. · Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts. · University of Nebraska Medical Centre, Omaha, Nebraska. · Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada13Molecular Genetics Department, University of Toronto, Toronto, Ontario, Canada. · Division of Medical Oncology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada. · Hepatobiliary/Pancreatic Surgical Oncology Program, University Health Network, Toronto, Ontario, Canada. · Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada15Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada15Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada16Department of Pathology, University Health Network, Toronto, Ontario, Canada17Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada18BioSpecimen Sciences Program, University Health Network, Toronto, Ontario, Canada. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada3Hepatobiliary/Pancreatic Surgical Oncology Program, University Health Network, Toronto, Ontario, Canada. · Theoretical Biology and Biophysics (T-6), Los Alamos National Laboratory, Los Alamos, New Mexico20Center for Nonlinear Studies, Los Alamos National Laboratory, Los Alamos, New Mexico. · Department of Pathology, University Health Network, Toronto, Ontario, Canada. · Genome Technologies Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada17Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. · Informatics and Bio-computing Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada13Molecular Genetics Department, University of Toronto, Toronto, Ontario, Canada. ·JAMA Oncol · Pubmed #27768182.

ABSTRACT: Importance: Outcomes for patients with pancreatic ductal adenocarcinoma (PDAC) remain poor. Advances in next-generation sequencing provide a route to therapeutic approaches, and integrating DNA and RNA analysis with clinicopathologic data may be a crucial step toward personalized treatment strategies for this disease. Objective: To classify PDAC according to distinct mutational processes, and explore their clinical significance. Design, Setting, and Participants: We performed a retrospective cohort study of resected PDAC, using cases collected between 2008 and 2015 as part of the International Cancer Genome Consortium. The discovery cohort comprised 160 PDAC cases from 154 patients (148 primary; 12 metastases) that underwent tumor enrichment prior to whole-genome and RNA sequencing. The replication cohort comprised 95 primary PDAC cases that underwent whole-genome sequencing and expression microarray on bulk biospecimens. Main Outcomes and Measures: Somatic mutations accumulate from sequence-specific processes creating signatures detectable by DNA sequencing. Using nonnegative matrix factorization, we measured the contribution of each signature to carcinogenesis, and used hierarchical clustering to subtype each cohort. We examined expression of antitumor immunity genes across subtypes to uncover biomarkers predictive of response to systemic therapies. Results: The discovery cohort was 53% male (n = 79) and had a median age of 67 (interquartile range, 58-74) years. The replication cohort was 50% male (n = 48) and had a median age of 68 (interquartile range, 60-75) years. Five predominant mutational subtypes were identified that clustered PDAC into 4 major subtypes: age related, double-strand break repair, mismatch repair, and 1 with unknown etiology (signature 8). These were replicated and validated. Signatures were faithfully propagated from primaries to matched metastases, implying their stability during carcinogenesis. Twelve of 27 (45%) double-strand break repair cases lacked germline or somatic events in canonical homologous recombination genes-BRCA1, BRCA2, or PALB2. Double-strand break repair and mismatch repair subtypes were associated with increased expression of antitumor immunity, including activation of CD8-positive T lymphocytes (GZMA and PRF1) and overexpression of regulatory molecules (cytotoxic T-lymphocyte antigen 4, programmed cell death 1, and indolamine 2,3-dioxygenase 1), corresponding to higher frequency of somatic mutations and tumor-specific neoantigens. Conclusions and Relevance: Signature-based subtyping may guide personalized therapy of PDAC in the context of biomarker-driven prospective trials.

11 Article A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns. 2016

Notta, Faiyaz / Chan-Seng-Yue, Michelle / Lemire, Mathieu / Li, Yilong / Wilson, Gavin W / Connor, Ashton A / Denroche, Robert E / Liang, Sheng-Ben / Brown, Andrew M K / Kim, Jaeseung C / Wang, Tao / Simpson, Jared T / Beck, Timothy / Borgida, Ayelet / Buchner, Nicholas / Chadwick, Dianne / Hafezi-Bakhtiari, Sara / Dick, John E / Heisler, Lawrence / Hollingsworth, Michael A / Ibrahimov, Emin / Jang, Gun Ho / Johns, Jeremy / Jorgensen, Lars G T / Law, Calvin / Ludkovski, Olga / Lungu, Ilinca / Ng, Karen / Pasternack, Danielle / Petersen, Gloria M / Shlush, Liran I / Timms, Lee / Tsao, Ming-Sound / Wilson, Julie M / Yung, Christina K / Zogopoulos, George / Bartlett, John M S / Alexandrov, Ludmil B / Real, Francisco X / Cleary, Sean P / Roehrl, Michael H / McPherson, John D / Stein, Lincoln D / Hudson, Thomas J / Campbell, Peter J / Gallinger, Steven. ·Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada. · Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK. · UHN Program in BioSpecimen Sciences, Department of Pathology, University Health Network, Toronto, Ontario M5G 2C4, Canada. · Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1L7, Canada. · Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada. · Department of Computer Science, University of Toronto, Toronto, Ontario M5S 3G4, Canada. · Eppley Institute for Research in Cancer, Nebraska Medical Center, Omaha, Nebraska 68198, USA. · Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada. · Princess Margaret Cancer Centre, University Health Network (UHN), Toronto, Ontario M5G 2M9, Canada. · Division of Surgical Oncology, Sunnybrook Health Sciences Centre, Odette Cancer Centre, Toronto, Ontario M4N 3M5, Canada. · Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota 55905, USA. · Research Institute of the McGill University Health Centre, Montreal, Québec, Canada, H3H 2L9. · Theoretical Biology and Biophysics (T-6) and Center for Nonlinear Studies, Los Alamos National Laboratory, Los Alamos, New Mexico, USA, 87545. · Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain. · Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada. · Department of Surgery, University Health Network, Toronto, Ontario M5G 2C4, Canada. · Department of Haematology, University of Cambridge, Cambridge CB2 0XY, UK. ·Nature · Pubmed #27732578.

ABSTRACT: Pancreatic cancer, a highly aggressive tumour type with uniformly poor prognosis, exemplifies the classically held view of stepwise cancer development. The current model of tumorigenesis, based on analyses of precursor lesions, termed pancreatic intraepithelial neoplasm (PanINs) lesions, makes two predictions: first, that pancreatic cancer develops through a particular sequence of genetic alterations (KRAS, followed by CDKN2A, then TP53 and SMAD4); and second, that the evolutionary trajectory of pancreatic cancer progression is gradual because each alteration is acquired independently. A shortcoming of this model is that clonally expanded precursor lesions do not always belong to the tumour lineage, indicating that the evolutionary trajectory of the tumour lineage and precursor lesions can be divergent. This prevailing model of tumorigenesis has contributed to the clinical notion that pancreatic cancer evolves slowly and presents at a late stage. However, the propensity for this disease to rapidly metastasize and the inability to improve patient outcomes, despite efforts aimed at early detection, suggest that pancreatic cancer progression is not gradual. Here, using newly developed informatics tools, we tracked changes in DNA copy number and their associated rearrangements in tumour-enriched genomes and found that pancreatic cancer tumorigenesis is neither gradual nor follows the accepted mutation order. Two-thirds of tumours harbour complex rearrangement patterns associated with mitotic errors, consistent with punctuated equilibrium as the principal evolutionary trajectory. In a subset of cases, the consequence of such errors is the simultaneous, rather than sequential, knockout of canonical preneoplastic genetic drivers that are likely to set-off invasive cancer growth. These findings challenge the current progression model of pancreatic cancer and provide insights into the mutational processes that give rise to these aggressive tumours.

12 Article Oncofetal Chondroitin Sulfate Glycosaminoglycans Are Key Players in Integrin Signaling and Tumor Cell Motility. 2016

Clausen, Thomas Mandel / Pereira, Marina Ayres / Al Nakouzi, Nader / Oo, Htoo Zarni / Agerbæk, Mette Ø / Lee, Sherry / Ørum-Madsen, Maj Sofie / Kristensen, Anders Riis / El-Naggar, Amal / Grandgenett, Paul M / Grem, Jean L / Hollingsworth, Michael A / Holst, Peter J / Theander, Thor / Sorensen, Poul H / Daugaard, Mads / Salanti, Ali. ·Centre for Medical Parasitology at Department of International Health, Immunology and Microbiology, University of Copenhagen, Denmark. tmc@sund.ku.dk mads.daugaard@ubc.ca salanti@sund.ku.dk. · Vancouver Prostate Centre, Vancouver, British Columbia, Canada. · Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada. · Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada. · Centre for Medical Parasitology at Department of International Health, Immunology and Microbiology, University of Copenhagen, Denmark. · Molecular Pathology and Cell Imaging Laboratory, Vancouver Prostate Centre, Vancouver, British Columbia, Canada. · Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska. · Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska. · Vancouver Prostate Centre, Vancouver, British Columbia, Canada. tmc@sund.ku.dk mads.daugaard@ubc.ca salanti@sund.ku.dk. ·Mol Cancer Res · Pubmed #27655130.

ABSTRACT: Many tumors express proteoglycans modified with oncofetal chondroitin sulfate glycosaminoglycan chains (ofCS), which are normally restricted to the placenta. However, the role of ofCS in cancer is largely unknown. The function of ofCS in cancer was analyzed using the recombinant ofCS-binding VAR2CSA protein (rVAR2) derived from the malaria parasite, Plasmodium falciparum We demonstrate that ofCS plays a key role in tumor cell motility by affecting canonical integrin signaling pathways. Binding of rVAR2 to tumor cells inhibited the interaction of cells with extracellular matrix (ECM) components, which correlated with decreased phosphorylation of Src kinase. Moreover, rVAR2 binding decreased migration, invasion, and anchorage-independent growth of tumor cells in vitro Mass spectrometry of ofCS-modified proteoglycan complexes affinity purified from tumor cell lines on rVAR2 columns revealed an overrepresentation of proteins involved in cell motility and integrin signaling, such as integrin-β1 (ITGB1) and integrin-α4 (ITGA4). Saturating concentrations of rVAR2 inhibited downstream integrin signaling, which was mimicked by knockdown of the core chondroitin sulfate synthesis enzymes β-1,3-glucuronyltransferase 1 (B3GAT1) and chondroitin sulfate N-acetylgalactosaminyltransferase 1 (CSGALNACT1). The ofCS modification was highly expressed in both human and murine metastatic lesions in situ and preincubation or early intravenous treatment of tumor cells with rVAR2 inhibited seeding and spreading of tumor cells in mice. This was associated with a significant increase in survival of the animals. These data functionally link ofCS modifications with cancer cell motility and further highlights ofCS as a novel therapeutic cancer target. IMPLICATIONS: The cancer-specific expression of ofCS aids in metastatic phenotypes and is a candidate target for therapy. Mol Cancer Res; 14(12); 1288-99. ©2016 AACR.

13 Article The small heat shock protein αA-crystallin negatively regulates pancreatic tumorigenesis. 2016

Liu, Jifang / Luo, Zhongwen / Zhang, Lan / Wang, Ling / Nie, Qian / Wang, Zheng-Feng / Huang, Zhaoxia / Hu, Xiaohui / Gong, Lili / Arrigo, Andre-Patrick / Tang, Xiangcheng / Xiang, Jia-Wen / Liu, Fangyuan / Deng, Mi / Ji, Weike / Hu, Wenfeng / Zhu, Ji-Ye / Chen, Baojiang / Bridge, Julia / Hollingsworth, Michael A / Gigantelli, James / Liu, Yizhi / Nguyen, Quan D / Li, David Wan-Cheng. ·State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong, 510060, China. · Institute of Cancer Research, The Affiliated Tumor Hospital of Guangzhou Medical College, Guangzhou, Guangdong 510095, China. · Department of Ophthalmology & Visual Sciences, Truhlsen Eye Institute, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA. · Key Laboratory of Protein Chemistry and Developmental Biology, College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, China. · Hepatobiliary Surgery Center of Peking University People's Hospital, Peking University, Beijing 100044, China. · Department of Biostatistics, College of Public Health, University of Nebraska Medical Center, Omaha, NE 68198, USA. · Department of Microbiology and Pathology, University of Nebraska Medical Center, Omaha, NE 68198, USA. · Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA. ·Oncotarget · Pubmed #27588467.

ABSTRACT: Our recent study has shown that αA-crystallin appears to act as a tumor suppressor in pancreas. Here, we analyzed expression patterns of αA-crystallin in the pancreatic tumor tissue and the neighbor normal tissue from 74 pancreatic cancer patients and also pancreatic cancer cell lines. Immunocytochemistry revealed that αA-crystallin was highly expressed in the normal tissue from 56 patients, but barely detectable in the pancreatic tumor tissue. Moreover, a low level of αA-crystallin predicts poor prognosis for patients with pancreatic duct adenocarcinoma (PDAC). In the 12 pancreatic cell lines analyzed, except for Capan-1 and Miapaca-2 where the level of αA-crystallin was about 80% and 65% of that in the control cell line, HPNE, the remaining pancreatic cancer cells have much lower αA-crystallin levels. Overexpression of αA-crystallin in MiaPaca-1 cells lacking endogenous αA-crystallin significantly decreased its tumorigenicity ability as shown in the colony formation and wound healing assays. In contrast, knockdown of αA-crystallin in the Capan-1 cells significantly increased its tumorigenicity ability as demonstrated in the above assays. Together, our results further demonstrate that αA-crystallin negatively regulates pancreatic tumorigenesis and appears to be a prognosis biomarker for PDAC.

14 Article Aberrant methylation of MUC1 and MUC4 promoters are potential prognostic biomarkers for pancreatic ductal adenocarcinomas. 2016

Yokoyama, Seiya / Higashi, Michiyo / Kitamoto, Sho / Oeldorf, Monika / Knippschild, Uwe / Kornmann, Marko / Maemura, Kosei / Kurahara, Hiroshi / Wiest, Edwin / Hamada, Tomofumi / Kitazono, Ikumi / Goto, Yuko / Tasaki, Takashi / Hiraki, Tsubasa / Hatanaka, Kazuhito / Mataki, Yuko / Taguchi, Hiroki / Hashimoto, Shinichi / Batra, Surinder K / Tanimoto, Akihide / Yonezawa, Suguru / Hollingsworth, Michael A. ·Department of Pathology, Research Field in Medicine and Health Sciences, Medical and Dental Sciences Area, Research and Education Assembly, Kagoshima University, Kagoshima, Japan. · Center for the Research of Advanced Diagnosis and Therapy of Cancer, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan. · Eppley Institute for Research in Cancer, Fred and Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA. · Department of General and Visceral Surgery, University of Ulm, Ulm, Germany. · Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Kagoshima, Japan. · Department of Oral Surgery, Kagoshima University Medical and Dental Hospital, Kagoshima, Japan. · Department of Digestive and Life-Style Related Diseases, Human and Environmental Sciences, Health Research, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan. · Department of Biochemistry and Molecular Biology, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA. ·Oncotarget · Pubmed #27283771.

ABSTRACT: Pancreatic cancer is still a disease of high mortality despite availability of diagnostic techniques. Mucins (MUC) play crucial roles in carcinogenesis and tumor invasion in pancreatic neoplasms. MUC1 and MUC4 are high molecular weight transmembrane mucins. These are overexpressed in many carcinomas, and high expression of these molecules is a risk factor associated with poor prognosis. We evaluated the methylation status of MUC1 and MUC4 promoter regions in pancreatic tissue samples from 169 patients with various pancreatic lesions by the methylation specific electrophoresis (MSE) method. These results were compared with expression of MUC1 and MUC4, several DNA methylation/demethylation factors (e.g. ten-eleven translocation or TET, and activation-induced cytidine deaminase or AID) and CAIX (carbonic anhydrase IX, as a hypoxia biomarker). These results were also analyzed with clinicopathological features including time of overall survival of PDAC patients. We show that the DNA methylation status of the promoters of MUC1 and MUC4 in pancreatic tissue correlates with the expression of MUC1 and MUC4 mRNA. In addition, the expression of several DNA methylation/demethylation factors show a significant correlation with MUC1 and MUC4 methylation status. Furthermore, CAIX expression significantly correlates with the expression of MUC1 and MUC4. Interestingly, our results indicate that low methylation of MUC1 and/or MUC4 promoters correlates with decreased overall survival. This is the first report to show a relationship between MUC1 and/or MUC4 methylation status and prognosis. Analysis of epigenetic changes in mucin genes may be of diagnostic utility and one of the prognostic predictors for patients with PDAC.

15 Article Image-based detection and targeting of therapy resistance in pancreatic adenocarcinoma. 2016

Fox, Raymond G / Lytle, Nikki K / Jaquish, Dawn V / Park, Frederick D / Ito, Takahiro / Bajaj, Jeevisha / Koechlein, Claire S / Zimdahl, Bryan / Yano, Masato / Kopp, Janel / Kritzik, Marcie / Sicklick, Jason / Sander, Maike / Grandgenett, Paul M / Hollingsworth, Michael A / Shibata, Shinsuke / Pizzo, Donald / Valasek, Mark / Sasik, Roman / Scadeng, Miriam / Okano, Hideyuki / Kim, Youngsoo / MacLeod, A Robert / Lowy, Andrew M / Reya, Tannishtha. ·Departments of Pharmacology and Medicine, University of California San Diego School of Medicine La Jolla, CA. · Sanford Consortium for Regenerative Medicine, La Jolla, CA. · Moores Cancer Center, University of California San Diego School of Medicine, La Jolla, CA. · Department of Surgery, Division of Surgical Oncology, University of California San Diego School of Medicine, La Jolla, CA. · Department of Medicine, Division of Gastroenterology, University of California San Diego School of Medicine, La Jolla, CA. · Department of Physiology, Graduate School of Medicine, Keio University, Keio, Japan. · Department of Cellular and Molecular Medicine, University of California San Diego School of Medicine, La Jolla, CA. · Eppley Institute For Research in Cancer and Allied Diseases, Department of Pathology, University of Nebraska Medical Center, Omaha, NE. · Department of Pathology, University of California San Diego School of Medicine, La Jolla, CA. · Center for Computational Biology and Bioinformatics, University of California San Diego School of Medicine, La Jolla, CA. · Department of Radiology, University of California San Diego School of Medicine, La Jolla, CA. · Department of Oncology Drug Discovery, Ionis pharmaceuticals, Carlsbad, CA. ·Nature · Pubmed #27281208.

ABSTRACT: Pancreatic intraepithelial neoplasia is a pre-malignant lesion that can progress to pancreatic ductal adenocarcinoma, a highly lethal malignancy marked by its late stage at clinical presentation and profound drug resistance. The genomic alterations that commonly occur in pancreatic cancer include activation of KRAS2 and inactivation of p53 and SMAD4 (refs 2-4). So far, however, it has been challenging to target these pathways therapeutically; thus the search for other key mediators of pancreatic cancer growth remains an important endeavour. Here we show that the stem cell determinant Musashi (Msi) is a critical element of pancreatic cancer progression both in genetic models and in patient-derived xenografts. Specifically, we developed Msi reporter mice that allowed image-based tracking of stem cell signals within cancers, revealing that Msi expression rises as pancreatic intraepithelial neoplasia progresses to adenocarcinoma, and that Msi-expressing cells are key drivers of pancreatic cancer: they preferentially harbour the capacity to propagate adenocarcinoma, are enriched in circulating tumour cells, and are markedly drug resistant. This population could be effectively targeted by deletion of either Msi1 or Msi2, which led to a striking defect in the progression of pancreatic intraepithelial neoplasia to adenocarcinoma and an improvement in overall survival. Msi inhibition also blocked the growth of primary patient-derived tumours, suggesting that this signal is required for human disease. To define the translational potential of this work we developed antisense oligonucleotides against Msi; these showed reliable tumour penetration, uptake and target inhibition, and effectively blocked pancreatic cancer growth. Collectively, these studies highlight Msi reporters as a unique tool to identify therapy resistance, and define Msi signalling as a central regulator of pancreatic cancer.

16 Article Identification of FRA-1 as a novel player in pancreatic cancer in cooperation with a MUC1: ERK signaling axis. 2016

Hanson, Ryan L / Brown, Roger B / Steele, Maria M / Grandgenett, Paul M / Grunkemeyer, James A / Hollingsworth, Michael A. ·Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA. · University of New Mexico, Albuquerque, NM 87131, USA. ·Oncotarget · Pubmed #27220889.

ABSTRACT: The MUC1 glycoprotein is overexpressed and aberrantly glycosylated in >90% of pancreatic ductal adenocarcinoma cases and impacts tumor progression by initiating downstream signaling through phosphorylation of its cytoplasmic tail. Previous studies have demonstrated that MUC1 alters expression of known targets of activator protein 1 (AP-1); however, no studies have evaluated the precise impact of MUC1 signaling on the activity and formation of AP-1. Given the known role of these proteins in modulating migration, invasion, and tumor progression, we explored the effects of MUC1 on AP-1 dimer formation and function. We determined that MUC1 increased the protein levels of c-Jun, the major component of AP-1, and promoted dimerization of c-Jun with the Fos-protein FRA-1. We demonstrate that FRA-1 acts as a potent mediator of migration and invasion in a manner that is modulated by signals through MUC1, which acts as a dominant regulator of specific AP-1 and FRA-1 target genes. Our results provide the first in vivo evidence of a FRA-1 mediated expression profile that impacts pancreatic tumor growth properties. In summary, we show that MUC1 enhancement of ERK activation influences FRA-1 activity to modulate tumor migration, invasion and metastasis in a subset of pancreatic cancer cases.

17 Article SOX2 functions as a molecular rheostat to control the growth, tumorigenicity and drug responses of pancreatic ductal adenocarcinoma cells. 2016

Wuebben, Erin L / Wilder, Phillip J / Cox, Jesse L / Grunkemeyer, James A / Caffrey, Thomas / Hollingsworth, Michael A / Rizzino, Angie. ·Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198-5950, USA. · Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska 68198-3135, USA. · Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska 68198-5870, USA. ·Oncotarget · Pubmed #27145457.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is a highly deadly malignancy. Expression of the stem cell transcription factor SOX2 increases during progression of PDAC. Knockdown of SOX2 in PDAC cell lines decreases growth in vitro; whereas, stable overexpression of SOX2 in one PDAC cell line reportedly increases growth in vitro. Here, we reexamined the role of SOX2 in PDAC cells, because inducible SOX2 overexpression in other tumor cell types inhibits growth. In this study, four PDAC cell lines were engineered for inducible overexpression of SOX2 or inducible knockdown of SOX2. Remarkably, inducible overexpression of SOX2 in PDAC cells inhibits growth in vitro and reduces tumorigenicity. Additionally, inducible knockdown of SOX2 in PDAC cells reduces growth in vitro and in vivo. Thus, growth and tumorigenicity of PDAC cells is highly dependent on the expression of optimal levels of SOX2 - a hallmark of molecular rheostats. We also determined that SOX2 alters the responses of PDAC cells to drugs used in PDAC clinical trials. Increasing SOX2 reduces growth inhibition mediated by MEK and AKT inhibitors; whereas knockdown of SOX2 further reduces growth when PDAC cells are treated with these inhibitors. Thus, targeting SOX2, or its mode of action, could improve the treatment of PDAC.

18 Article Proteomic mapping of p53 immunogenicity in pancreatic, ovarian, and breast cancers. 2016

Katchman, Benjamin A / Barderas, Rodrigo / Alam, Rizwan / Chowell, Diego / Field, Matthew S / Esserman, Laura J / Wallstrom, Garrick / LaBaer, Joshua / Cramer, Daniel W / Hollingsworth, Michael A / Anderson, Karen S. ·Virginia G. Piper Center for Personalized Diagnostics, Biodesign Institute, Arizona State University, Tempe, AZ, USA. · Biochemistry and Molecular Biology I Department, Complutense University, Madrid, Spain. · Department of Surgery, University of California, San Francisco, CA, USA. · Department of Gynecology and Reproductive Biology, Brigham and Women's Hospital, Boston, MA. · Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, USA. ·Proteomics Clin Appl · Pubmed #27121307.

ABSTRACT: PURPOSE: Mutations in TP53 induce autoantibody immune responses in a subset of cancer patients, which have been proposed as biomarkers for early detection. Here, we investigate the association of p53-specific autoantibodies with multiple tumor subtypes and determine the association with p53 mutation status and epitope specificity. EXPERIMENTAL DESIGN: IgG p53 autoantibodies (p53-AAb), were quantified in 412 serum samples using a programmable ELISA assay from patients with serous ovarian, pancreatic adenocarcinoma, and breast cancer. To determine if patients generated mutation-specific autoantibodies we designed a panel of the most relevant 51 p53 point mutant proteins, to be displayed on custom programmable protein microarrays. To determine the epitope specificity we displayed 12 overlapping tiling fragments and 38 N- and C-terminal deletions spanning the length of the wild-type p53 protein. RESULTS: We detected p53-AAb with sensitivities of 58.8% (ovarian), 22% (pancreatic), 32% (triple negative breast cancer), and 10.2% (HER2+ breast cancer) at 94% specificity. Sera with p53-AAb contained broadly reactive autoantibodies to 51 displayed p53 mutant proteins, demonstrating a polyclonal response to common epitopes. All p53-AAb displayed broad polyclonal immune response to both continuous and discontinuous epitopes at the N- and C-terminus as well as the DNA-binding domain. CONCLUSION AND CLINICAL RELEVANCE: In this comprehensive analysis, mutations in tumor p53 induce strong, polyclonal autoantibodies with broadly reactive epitope specificity.

19 Article Definitive Characterization of CA 19-9 in Resectable Pancreatic Cancer Using a Reference Set of Serum and Plasma Specimens. 2015

Haab, Brian B / Huang, Ying / Balasenthil, Seetharaman / Partyka, Katie / Tang, Huiyuan / Anderson, Michelle / Allen, Peter / Sasson, Aaron / Zeh, Herbert / Kaul, Karen / Kletter, Doron / Ge, Shaokui / Bern, Marshall / Kwon, Richard / Blasutig, Ivan / Srivastava, Sudhir / Frazier, Marsha L / Sen, Subrata / Hollingsworth, Michael A / Rinaudo, Jo Ann / Killary, Ann M / Brand, Randall E. ·Van Andel Research Institute, Grand Rapids, MI, United States of America. · Fred Hutchinson Cancer Research Center, Seattle, WA, United States of America. · The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America. · University of Michigan, Ann Arbor, MI, United States of America. · Memorial Sloan Kettering Cancer Center, New York, NY, United States of America. · University of Nebraska Medical Center, Omaha, NE, United States of America. · University of Pittsburgh Medical Center, Pittsburgh, PA, United States of America. · Northshore University Healthsystems, Evanston, IL, United States of America. · Palo Alto Research Center, Palo Alto, CA, United States of America. · University Health Network, Toronto, ON, Canada. · National Cancer Institute, Rockville, MD, United States of America. ·PLoS One · Pubmed #26431551.

ABSTRACT: The validation of candidate biomarkers often is hampered by the lack of a reliable means of assessing and comparing performance. We present here a reference set of serum and plasma samples to facilitate the validation of biomarkers for resectable pancreatic cancer. The reference set includes a large cohort of stage I-II pancreatic cancer patients, recruited from 5 different institutions, and relevant control groups. We characterized the performance of the current best serological biomarker for pancreatic cancer, CA 19-9, using plasma samples from the reference set to provide a benchmark for future biomarker studies and to further our knowledge of CA 19-9 in early-stage pancreatic cancer and the control groups. CA 19-9 distinguished pancreatic cancers from the healthy and chronic pancreatitis groups with an average sensitivity and specificity of 70-74%, similar to previous studies using all stages of pancreatic cancer. Chronic pancreatitis patients did not show CA 19-9 elevations, but patients with benign biliary obstruction had elevations nearly as high as the cancer patients. We gained additional information about the biomarker by comparing two distinct assays. The two CA 9-9 assays agreed well in overall performance but diverged in measurements of individual samples, potentially due to subtle differences in antibody specificity as revealed by glycan array analysis. Thus, the reference set promises be a valuable resource for biomarker validation and comparison, and the CA 19-9 data presented here will be useful for benchmarking and for exploring relationships to CA 19-9.

20 Article Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma. 2015

Moffitt, Richard A / Marayati, Raoud / Flate, Elizabeth L / Volmar, Keith E / Loeza, S Gabriela Herrera / Hoadley, Katherine A / Rashid, Naim U / Williams, Lindsay A / Eaton, Samuel C / Chung, Alexander H / Smyla, Jadwiga K / Anderson, Judy M / Kim, Hong Jin / Bentrem, David J / Talamonti, Mark S / Iacobuzio-Donahue, Christine A / Hollingsworth, Michael A / Yeh, Jen Jen. ·Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA. · University of North Carolina-Rex Healthcare, Chapel Hill, North Carolina, USA. · Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA. · Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA. · Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina, USA. · Eppley Cancer Institute, University of Nebraska, Lincoln, Nebraska, USA. · Department of Surgery, University of North Carolina, Chapel Hill, North Carolina, USA. · Department of Surgery, Feinberg School of Medicine Northwestern University, Chicago, Illinois, USA. · Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine Northwestern University, Chicago, Illinois, USA. · Department of Surgery, NorthShore University HealthSystem, Evanston, Illinois, USA. · Department of Pathology, David Rubenstein Center for Pancreatic Cancer Research, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA. ·Nat Genet · Pubmed #26343385.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) remains a lethal disease with a 5-year survival rate of 4%. A key hallmark of PDAC is extensive stromal involvement, which makes capturing precise tumor-specific molecular information difficult. Here we have overcome this problem by applying blind source separation to a diverse collection of PDAC gene expression microarray data, including data from primary tumor, metastatic and normal samples. By digitally separating tumor, stromal and normal gene expression, we have identified and validated two tumor subtypes, including a 'basal-like' subtype that has worse outcome and is molecularly similar to basal tumors in bladder and breast cancers. Furthermore, we define 'normal' and 'activated' stromal subtypes, which are independently prognostic. Our results provide new insights into the molecular composition of PDAC, which may be used to tailor therapies or provide decision support in a clinical setting where the choice and timing of therapies are critical.

21 Article Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver. 2015

Costa-Silva, Bruno / Aiello, Nicole M / Ocean, Allyson J / Singh, Swarnima / Zhang, Haiying / Thakur, Basant Kumar / Becker, Annette / Hoshino, Ayuko / Mark, Milica Tešić / Molina, Henrik / Xiang, Jenny / Zhang, Tuo / Theilen, Till-Martin / García-Santos, Guillermo / Williams, Caitlin / Ararso, Yonathan / Huang, Yujie / Rodrigues, Gonçalo / Shen, Tang-Long / Labori, Knut Jørgen / Lothe, Inger Marie Bowitz / Kure, Elin H / Hernandez, Jonathan / Doussot, Alexandre / Ebbesen, Saya H / Grandgenett, Paul M / Hollingsworth, Michael A / Jain, Maneesh / Mallya, Kavita / Batra, Surinder K / Jarnagin, William R / Schwartz, Robert E / Matei, Irina / Peinado, Héctor / Stanger, Ben Z / Bromberg, Jacqueline / Lyden, David. ·Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medical College, New York, New York 10021, USA. · Gastroenterology Division, Department of Medicine, Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia 19104, USA. · Department of Medicine, Division of Hematology and Medical Oncology, New York Presbyterian Hospital, Weill Cornell Medical College, New York, New York 10021, USA. · 1] Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medical College, New York, New York 10021, USA [2] Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover 30625, Germany. · Proteomics Resource Center, The Rockefeller University, New York, New York 10065, USA. · Genomics Resources Core Facility, Weill Cornell Medical College, New York, New York 10021, USA. · 1] Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medical College, New York, New York 10021, USA [2] Graduate Program in Areas of Basic and Applied Biology, Abel Salazar Biomedical Sciences Institute, University of Porto, 4099-003 Porto, Portugal. · Department of Plant Pathology and Microbiology, National Taiwan University, Taipei 10617, Taiwan. · Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Nydalen, Oslo 0424, Norway. · 1] Department of Pathology, Oslo University Hospital, Nydalen, Oslo 0424, Norway [2] Department of Genetics, Institute for Cancer Research, Oslo University Hospital, Nydalen, Oslo 0424, Norway. · Department of Genetics, Institute for Cancer Research, Oslo University Hospital, Nydalen, Oslo 0424, Norway. · Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. · Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA. · Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA. · Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medical College, New York, New York 10021, USA. · 1] Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medical College, New York, New York 10021, USA [2] Microenvironment and Metastasis Laboratory, Department of Molecular Oncology, Spanish National Cancer Research Center (CNIO), Madrid 28029, Spain. · Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, New York 10065, USA. · 1] Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medical College, New York, New York 10021, USA [2] Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ·Nat Cell Biol · Pubmed #25985394.

ABSTRACT: Pancreatic ductal adenocarcinomas (PDACs) are highly metastatic with poor prognosis, mainly due to delayed detection. We hypothesized that intercellular communication is critical for metastatic progression. Here, we show that PDAC-derived exosomes induce liver pre-metastatic niche formation in naive mice and consequently increase liver metastatic burden. Uptake of PDAC-derived exosomes by Kupffer cells caused transforming growth factor β secretion and upregulation of fibronectin production by hepatic stellate cells. This fibrotic microenvironment enhanced recruitment of bone marrow-derived macrophages. We found that macrophage migration inhibitory factor (MIF) was highly expressed in PDAC-derived exosomes, and its blockade prevented liver pre-metastatic niche formation and metastasis. Compared with patients whose pancreatic tumours did not progress, MIF was markedly higher in exosomes from stage I PDAC patients who later developed liver metastasis. These findings suggest that exosomal MIF primes the liver for metastasis and may be a prognostic marker for the development of PDAC liver metastasis.

22 Article Amyloid precursor-like protein 2 (APLP2) affects the actin cytoskeleton and increases pancreatic cancer growth and metastasis. 2015

Pandey, Poomy / Rachagani, Satyanarayana / Das, Srustidhar / Seshacharyulu, Parthasarathy / Sheinin, Yuri / Naslavsky, Naava / Pan, Zenggang / Smith, Brittney L / Peters, Haley L / Radhakrishnan, Prakash / McKenna, Nicole R / Giridharan, Sai Srinivas Panapakkam / Haridas, Dhanya / Kaur, Sukhwinder / Hollingsworth, Michael A / MacDonald, Richard G / Meza, Jane L / Caplan, Steve / Batra, Surinder K / Solheim, Joyce C. ·Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA. · Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA. · Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA. · Department of Pathology, University of Colorado, Aurora, CO, USA. · Current addresses: Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston TX, USA. · Current addresses: School of Medicine, University of Virginia, Charlottesville, VA, USA. · Current addresses: Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA. · Department of Biostatistics, University of Nebraska Medical Center, Omaha, NE, USA. ·Oncotarget · Pubmed #25576918.

ABSTRACT: Amyloid precursor-like protein 2 (APLP2) is aberrantly expressed in pancreatic cancer. Here we showed that APLP2 is increased in pancreatic cancer metastases, particularly in metastatic lesions found in the diaphragm and intestine. Examination of matched human primary tumor-liver metastasis pairs showed that 38.1% of the patients had positive APLP2 expression in both the primary tumor and the corresponding liver metastasis. Stable knock-down of APLP2 expression (with inducible shRNA) in pancreatic cancer cells reduced the ability of these cells to migrate and invade. Loss of APLP2 decreased cortical actin and increased intracellular actin filaments in pancreatic cancer cells. Down-regulation of APLP2 decreased the weight and metastasis of orthotopically transplanted pancreatic tumors in nude mice.

23 Article Spatiotemporal proteomic analyses during pancreas cancer progression identifies serine/threonine stress kinase 4 (STK4) as a novel candidate biomarker for early stage disease. 2014

Mirus, Justin E / Zhang, Yuzheng / Hollingsworth, Michael A / Solan, Joell L / Lampe, Paul D / Hingorani, Sunil R. ·From the ‡Translational Research Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109; §Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109; · From the ‡Translational Research Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109; · ¶Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198; · From the ‡Translational Research Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109; §Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109; plampe@fhcrc.org srh@fhcrc.org. · From the ‡Translational Research Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109; **Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109; ‡‡Division of Medical Oncology, University of Washington School of Medicine, Seattle, Washington 98195 plampe@fhcrc.org srh@fhcrc.org. ·Mol Cell Proteomics · Pubmed #25225358.

ABSTRACT: Pancreas cancer, or pancreatic ductal adenocarcinoma, is the deadliest of solid tumors, with a five-year survival rate of <5%. Detection of resectable disease improves survival rates, but access to tissue and other biospecimens that could be used to develop early detection markers is confounded by the insidious nature of pancreas cancer. Mouse models that accurately recapitulate the human condition allow disease tracking from inception to invasion and can therefore be useful for studying early disease stages in which surgical resection is possible. Using a highly faithful mouse model of pancreas cancer in conjunction with a high-density antibody microarray containing ∼2500 antibodies, we interrogated the pancreatic tissue proteome at preinvasive and invasive stages of disease. The goal was to discover early stage tissue markers of pancreas cancer and follow them through histologically defined stages of disease using cohorts of mice lacking overt clinical signs and symptoms and those with end-stage metastatic disease, respectively. A panel of seven up-regulated proteins distinguishing pancreas cancer from normal pancreas was validated, and their levels were assessed in tissues collected at preinvasive, early invasive, and moribund stages of disease. Six of the seven markers also differentiated pancreas cancer from an experimental model of chronic pancreatitis. The levels of serine/threonine stress kinase 4 (STK4) increased between preinvasive and invasive stages, suggesting its potential as a tissue biomarker, and perhaps its involvement in progression from precursor pancreatic intraepithelial neoplasia to pancreatic ductal adenocarcinoma. Immunohistochemistry of STK4 at different stages of disease revealed a dynamic expression pattern further implicating it in early tumorigenic events. Immunohistochemistry of a panel of human pancreas cancers confirmed that STK4 levels were increased in tumor epithelia relative to normal tissue. Overall, this integrated approach yielded several tissue markers that could serve as signatures of disease stage, including early (resectable), and therefore clinically meaningful, stages.

24 Article Immature truncated O-glycophenotype of cancer directly induces oncogenic features. 2014

Radhakrishnan, Prakash / Dabelsteen, Sally / Madsen, Frey Brus / Francavilla, Chiara / Kopp, Katharina L / Steentoft, Catharina / Vakhrushev, Sergey Y / Olsen, Jesper V / Hansen, Lars / Bennett, Eric P / Woetmann, Anders / Yin, Guangliang / Chen, Longyun / Song, Haiyan / Bak, Mads / Hlady, Ryan A / Peters, Staci L / Opavsky, Rene / Thode, Christenze / Qvortrup, Klaus / Schjoldager, Katrine T-B G / Clausen, Henrik / Hollingsworth, Michael A / Wandall, Hans H. ·Eppley Institute for Research in Cancer, Fred and Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198-5950; · Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, Department of Pathology and Medicine, School of Dentistry. · Protein Center. · Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine. · Department of Immunology, Faculty of Health Sciences, University of Copenhagen, DK-2200 Copenhagen N, Denmark; and. · BGI-Tech, BGI-Shenzhen, Shenzhen 518083, China. · Department of Pathology and Medicine, School of Dentistry. · Department of Biomedical Sciences/Core Facility for Integrated Microscopy, and. · Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, hhw@sund.ku.dk. ·Proc Natl Acad Sci U S A · Pubmed #25118277.

ABSTRACT: Aberrant expression of immature truncated O-glycans is a characteristic feature observed on virtually all epithelial cancer cells, and a very high frequency is observed in early epithelial premalignant lesions that precede the development of adenocarcinomas. Expression of the truncated O-glycan structures Tn and sialyl-Tn is strongly associated with poor prognosis and overall low survival. The genetic and biosynthetic mechanisms leading to accumulation of truncated O-glycans are not fully understood and include mutation or dysregulation of glycosyltransferases involved in elongation of O-glycans, as well as relocation of glycosyltransferases controlling initiation of O-glycosylation from Golgi to endoplasmic reticulum. Truncated O-glycans have been proposed to play functional roles for cancer-cell invasiveness, but our understanding of the biological functions of aberrant glycosylation in cancer is still highly limited. Here, we used exome sequencing of most glycosyltransferases in a large series of primary and metastatic pancreatic cancers to rule out somatic mutations as a cause of expression of truncated O-glycans. Instead, we found hypermethylation of core 1 β3-Gal-T-specific molecular chaperone, a key chaperone for O-glycan elongation, as the most prevalent cause. We next used gene editing to produce isogenic cell systems with and without homogenous truncated O-glycans that enabled, to our knowledge, the first polyomic and side-by-side evaluation of the cancer O-glycophenotype in an organotypic tissue model and in xenografts. The results strongly suggest that truncation of O-glycans directly induces oncogenic features of cell growth and invasion. The study provides support for targeting cancer-specific truncated O-glycans with immunotherapeutic measures.

25 Article Context-dependent function of the deubiquitinating enzyme USP9X in pancreatic ductal adenocarcinoma. 2014

Cox, Jesse L / Wilder, Phillip J / Wuebben, Erin L / Ouellette, Michel M / Hollingsworth, Michael A / Rizzino, Angie. ·Eppley Institute for Research in Cancer and Allied Diseases; Fred & Pamela Buffett Cancer Center; University of Nebraska Medical Center; Omaha, NE USA. ·Cancer Biol Ther · Pubmed #24841553.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and deadly malignancies. Recently, the deubiquitinating protease USP9X has been shown to behave as an oncogene in a number of neoplasms, including those of breast, brain, colon, esophagus and lung, as well as KRAS wild-type PDAC. However, other studies suggest that USP9X may function as a tumor-suppressor in a murine PDAC model when USP9X expression is depleted during early pancreatic development. To address the conflicting findings surrounding the role of USP9X in PDAC, we examined the effects of knocking down USP9X in five human PDAC cell lines (BxPC3, Capan1, CD18, Hs766T, and S2-013). We demonstrate that knocking down USP9X in each of the PDAC cell lines reduces their anchorage-dependent growth. Using an inducible shRNA system to knock down USP9X in both BxPC3 and Capan1 cells, we also determined that USP9X is necessary for the anchorage-independent growth. In addition, knockdown of USP9X alters the cell cycle profile of BxPC3 cells and increases their invasive capacity. Finally, we show that an inhibitor of deubiquitinating proteases, WP1130, induces significant cytotoxicity in each of the five PDAC cell lines tested. Overall, our work and the work of others indicate that the function and role of USP9X is highly context-dependent. Although USP9X may function as a tumor-suppressor during the establishment of PDAC, data presented here argue that USP9X promotes cell growth in advanced PDAC cells when PDAC is typically diagnosed. Hence, USP9X may be a promising therapeutic target for the treatment of advanced PDAC.

Next