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Pancreatic Neoplasms: HELP
Articles by David A. Tuveson
Based on 74 articles published since 2010
(Why 74 articles?)
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Between 2010 and 2020, D. Tuveson wrote the following 74 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3
1 Editorial ROS in translation: Chink in the armor. 2017

Chio, Iok In Christine / Tuveson, David A. ·a Cold Spring Harbor Laboratory , Cold Spring Harbor , NY , USA. · b Lustgarten Foundation Pancreatic Cancer Research Laboratory , Cold Spring Harbor , NY , USA. ·Cell Cycle · Pubmed #27636545.

ABSTRACT: -- No abstract --

2 Editorial MAX-ing out MYC: a novel small molecule inhibitor against MYC-dependent tumors. 2014

Chio, Iok In Christine / Yordanov, Georgi / Tuveson, David. ·Cold Spring Harbor Laboratory, Cold Spring Harbor, NY (IICC, GY, DT) · Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY (GY). ·J Natl Cancer Inst · Pubmed #25430851.

ABSTRACT: -- No abstract --

3 Review Pharmacokinetics and pharmacodynamics of new drugs for pancreatic cancer. 2019

Sugarman, Ryan / Patel, Rajvi / Sharma, Sandhya / Plenker, Dennis / Tuveson, David / Saif, Muhammad Wasif. ·a Northwell Health Cancer Institute , Donald and Barbara Zucker School of Medicine at Hofstra/Northwell , Lake Success , NY , USA. · b Cold Spring Harbor Laboratory , Cold Spring Harbor , NY , USA. ·Expert Opin Drug Metab Toxicol · Pubmed #31241371.

ABSTRACT:

4 Review Stromal biology and therapy in pancreatic cancer: ready for clinical translation? 2019

Neesse, Albrecht / Bauer, Christian Alexander / Öhlund, Daniel / Lauth, Matthias / Buchholz, Malte / Michl, Patrick / Tuveson, David A / Gress, Thomas M. ·Department of Gastroenterology and Gastrointestinal Oncology, University Medicine Goettingen, Goettingen, Germany. · Department of Gastroenterology, Endocrinology, Metabolism and Infectiology, University Hospital Marburg, UKGM, Philipps University Marburg, Marburg, Germany. · Department of Radiation Sciences, Umeå University, Umeå, Sweden. · Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden. · Department of Medicine, Philipps University, Center for Tumour and Immune Biology, Marburg, Germany. · Department of Internal Medicine I, Martin, Luther University Halle-Wittenberg, Halle, Germany. · Lustgarten Foundation Designated Pancreatic Cancer Research Lab at Cold Spring Harbor Laboratory, New York, USA. ·Gut · Pubmed #30177543.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDA) is notoriously aggressive and hard to treat. The tumour microenvironment (TME) in PDA is highly dynamic and has been found to promote tumour progression, metastasis niche formation and therapeutic resistance. Intensive research of recent years has revealed an incredible heterogeneity and complexity of the different components of the TME, including cancer-associated fibroblasts, immune cells, extracellular matrix components, tumour vessels and nerves. It has been hypothesised that paracrine interactions between neoplastic epithelial cells and TME compartments may result in either tumour-promoting or tumour-restraining consequences. A better preclinical understanding of such complex and dynamic network systems is required to develop more powerful treatment strategies for patients. Scientific activity and the number of compelling findings has virtually exploded during recent years. Here, we provide an update of the most recent findings in this area and discuss their translational and clinical implications for basic scientists and clinicians alike.

5 Review Kras in Organoids. 2018

Cheng, Derek / Tuveson, David. ·CSHL Cancer Center, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11743. ·Cold Spring Harb Perspect Med · Pubmed #29311127.

ABSTRACT: Oncogenic Kras are genetic dependencies for the majority of pancreatic and colorectal adenocarcinomas; however, much remains to be understood regarding its tropism to these carcinomas. Recently developed organoid technology presents a more representative model culture system for pancreatic and colon epithelial tissues as well as better fostering the culture of nonimmortalized cells than two-dimensional culture. These advantages enable cancer researchers to directly compare tumor and normal tissue models to better study tumor initiation as well as therapeutic efficacy. Although in vivo models better model the complexity of multiple cell types, the organoid system allows for easier genetic manipulations and isolation of specific cell types. Furthermore, syngeneic orthotopically transplanted organoids recapitulate tumor histologically and gene expression of the tumors from which they were derived. Thus, organoids may extend the use of genetically engineered mouse models. These advantages of organoid cultures allow for many questions, including but not limited to studying the interaction between different cell types within a tumor and elucidating dependencies of Kras-driven tumors.

6 Review Challenges and Opportunities in Modeling Pancreatic Cancer. 2016

Feigin, Michael E / Tuveson, David A. ·Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724. · Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, New York 11724. · Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York 10065. ·Cold Spring Harb Symp Quant Biol · Pubmed #28289164.

ABSTRACT: The ability to faithfully model complex processes lies at the heart of experimental biology. Although a reductionist approach necessarily reduces this complexity, it is nevertheless required for untangling the contributions and interactions of the various system components. It has long been appreciated that cancer is a complex process that involves positive and negative interactions between tumor cells, normal host tissue, and the associated cells of the tumor microenvironment. However, accurate models for studying these complex interactions in vitro have remained elusive. We seek to generate models of mouse and human pancreatic cancer that are relevant to disease biology and useful for elucidating poorly understood facets of this deadly disease. The ability to model, manipulate, and predict the therapeutic response of an individual's disease outside their body represents the promise of precision medicine. Therefore, these models are patient-specific and allow the identification of new biomarkers and novel treatment modalities for rapid translation to the clinic. In this perspective we will discuss recent advances in modeling pancreatic cancer in vitro, the discoveries these models have enabled, and future challenges and opportunities awaiting further investigation.

7 Review Pancreatic cancer. 2016

Kleeff, Jorg / Korc, Murray / Apte, Minoti / La Vecchia, Carlo / Johnson, Colin D / Biankin, Andrew V / Neale, Rachel E / Tempero, Margaret / Tuveson, David A / Hruban, Ralph H / Neoptolemos, John P. ·NIHR Pancreas Biomedical Research Unit, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Royal Liverpool and Broadgreen University Hospitals NHS Trust, Duncan Building, Daulby Street, Liverpool L69 3GA, UK. · Department of General, Visceral and Pediatric Surgery, University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany. · Departments of Medicine, and Biochemistry and Molecular Biology, Indiana University School of Medicine, the Melvin and Bren Simon Cancer Center, and the Pancreatic Cancer Signature Center, Indianapolis, Indiana, USA. · SWS Clinical School, University of New South Wales, and Ingham Institute for Applied Medical Research, Sydney, New South Wales, Australia. · Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy. · University Surgical Unit, University Hospital Southampton, Southampton, UK. · Institute of Cancer Sciences, Wolfson Wohl Cancer Research Centre, University of Glasgow, Garscube Estate, Bearsden, Glasgow, Scotland, UK. · QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. · UCSF Pancreas Center, University of California San Francisco - Mission Bay Campus/Mission Hall, San Francisco, California, USA. · Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, New York, USA. · The Sol Goldman Pancreatic Cancer Research Center, Departments of Pathology and Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. ·Nat Rev Dis Primers · Pubmed #27158978.

ABSTRACT: Pancreatic cancer is a major cause of cancer-associated mortality, with a dismal overall prognosis that has remained virtually unchanged for many decades. Currently, prevention or early diagnosis at a curable stage is exceedingly difficult; patients rarely exhibit symptoms and tumours do not display sensitive and specific markers to aid detection. Pancreatic cancers also have few prevalent genetic mutations; the most commonly mutated genes are KRAS, CDKN2A (encoding p16), TP53 and SMAD4 - none of which are currently druggable. Indeed, therapeutic options are limited and progress in drug development is impeded because most pancreatic cancers are complex at the genomic, epigenetic and metabolic levels, with multiple activated pathways and crosstalk evident. Furthermore, the multilayered interplay between neoplastic and stromal cells in the tumour microenvironment challenges medical treatment. Fewer than 20% of patients have surgically resectable disease; however, neoadjuvant therapies might shift tumours towards resectability. Although newer drug combinations and multimodal regimens in this setting, as well as the adjuvant setting, appreciably extend survival, ∼80% of patients will relapse after surgery and ultimately die of their disease. Thus, consideration of quality of life and overall survival is important. In this Primer, we summarize the current understanding of the salient pathophysiological, molecular, translational and clinical aspects of this disease. In addition, we present an outline of potential future directions for pancreatic cancer research and patient management.

8 Review Preclinical models of pancreatic ductal adenocarcinoma. 2016

Hwang, Chang-Il / Boj, Sylvia F / Clevers, Hans / Tuveson, David A. ·Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA. · Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY, USA. · Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW), University Medical Centre Utrecht and CancerGenomics.nl, Utrecht, The Netherlands. · foundation Hubrecht Organoid Technology (HUB), Utrecht, The Netherlands. · Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA. ·J Pathol · Pubmed #26419819.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDA) is one of the most difficult human malignancies to treat. The 5-year survival rate of PDA patients is 7% and PDA is predicted to become the second leading cancer-related cause of death in the USA. Despite intensive efforts, the translation of findings in preclinical studies has been ineffective, due partially to the lack of preclinical models that faithfully recapitulate features of human PDA. Here, we review current preclinical models for human PDA (eg human PDA cell lines, cell line-based xenografts and patient-derived tumour xenografts). In addition, we discuss potential applications of the recently developed pancreatic ductal organoids, three-dimensional culture systems and organoid-based xenografts as new preclinical models for PDA.

9 Review Mouse Models of Pancreatic Ductal Adenocarcinoma. 2015

Ponz-Sarvise, Mariano / Tuveson, David A / Yu, Kenneth H. ·Cancer Biology, Cold Spring Harbor Laboratory, One Bungtown Road, Cold Spring Harbor, NY 11724, USA. · Cancer Biology, Cold Spring Harbor Laboratory, One Bungtown Road, Cold Spring Harbor, NY 11724, USA; Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: dtuveson@cshl.edu. · Cancer Biology, Cold Spring Harbor Laboratory, One Bungtown Road, Cold Spring Harbor, NY 11724, USA; Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Weill Medical College, Cornell University, New York, NY 10065, USA. Electronic address: yuk1@mskcc.org. ·Hematol Oncol Clin North Am · Pubmed #26226900.

ABSTRACT: Only 10% to 15% of patients with pancreatic ductal adenocarcinoma (PDAC) are candidates for potentially curative surgery due to the location or spread of disease at the time of diagnosis. Despite rapid progress in the understanding of the molecular mechanisms underlying PDAC, translation to effective therapies has been modest at best. One of the key tools available for studying biology and developing more effective therapeutics is the laboratory mouse, mus musculus. This article explores new and innovative approaches to mouse modeling and how these approaches can be utilized to move the field forward.

10 Review Stromal biology and therapy in pancreatic cancer: a changing paradigm. 2015

Neesse, Albrecht / Algül, Hana / Tuveson, David A / Gress, Thomas M. ·Department of Gastroenterology and Gastrointestinal Oncology, University Medical Centre Goettingen, Georg August University Goettingen, Goettingen, Germany. · II. Medizinische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany. · Cold Spring Harbor Laboratory, Pancreatic Cancer Research Laboratory, Cold Spring Harbor, New York, USA. · Department of Gastroenterology, Endocrinology, Infectiology and Metabolism, Philipps-University, Marburg, Germany. ·Gut · Pubmed #25994217.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDA) exhibits one of the poorest prognosis of all solid tumours and poses an unsolved problem in cancer medicine. Despite the recent success of two combination chemotherapies for palliative patients, the modest survival benefits are often traded against significant side effects and a compromised quality of life. Although the molecular events underlying the initiation and progression of PDA have been intensively studied and are increasingly understood, the reasons for the poor therapeutic response are hardly apprehended. One leading hypothesis over the last few years has been that the pronounced tumour microenvironment in PDA not only promotes carcinogenesis and tumour progression but also mediates therapeutic resistance. To this end, targeting of various stromal components and pathways was considered a promising strategy to biochemically and biophysically enhance therapeutic response. However, none of the efforts have yet led to efficacious and approved therapies in patients. Additionally, recent data have shown that tumour-associated fibroblasts may restrain rather than promote tumour growth, reinforcing the need to critically revisit the complexity and complicity of the tumour-stroma with translational implications for future therapy and clinical trial design.

11 Review nab-Paclitaxel: novel clinical and experimental evidence in pancreatic cancer. 2014

Neesse, A / Michl, P / Tuveson, D A / Ellenrieder, V. ·Department of Gastroenterology, Endocrinology, Infectiology and Metabolism, Philipps University Marburg, Marburg, Germany. · Cold Spring Harbor, Laboratory Cold Spring Harbor, NY, USA. ·Z Gastroenterol · Pubmed #24687799.

ABSTRACT: The past few decades have seen virtually no treatment advances for patients with metastatic pancreatic cancer. Clinical hallmark features of pancreatic ductal adenocarcinoma (PDA) include late symptom onset, invasive growth, early liver and lymph node metastasis, and resistance to available chemotherapies. nab-Paclitaxel (Abraxane®) is generated through high-pressure homogenization of human albumin and conventional paclitaxel resulting in non-covalently bound, water-soluble albumin-paclitaxel particles with an approximate diameter of 130 nm. Results from the recently completed Metastatic Pancreatic Adenocarcinoma Trial (MPACT) (phase III trial) showed a significant survival benefit for patients treated with nab-paclitaxel in combination with gemcitabine, and this treatment regimen is currently being implemented in national and international guidelines for PDA patients. Therefore, this regimen provides a much needed vantage point of attack for this recalcitrant tumor offering potential new hope for our patients. Mechanisms such as stromal depletion, selective intratumoral accumulation, synergism with gemcitabine metabolism and secreted protein acidic and rich in cysteine (SPARC) mediated anti-tumor activity have been suggested for nab-paclitaxel. This review discusses the clinical and experimental advances of nab-paclitaxel in pancreatic cancer.

12 Review Emerging concepts in pancreatic cancer medicine: targeting the tumor stroma. 2013

Neesse, Albrecht / Krug, Sebastian / Gress, Thomas M / Tuveson, David A / Michl, Patrick. ·Department of Gastroenterology, Endocrinology, Infectiology and Metabolism, Philipps University Marburg, Marburg, Germany. · Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA. ·Onco Targets Ther · Pubmed #24379681.

ABSTRACT: Pancreatic ductal adenocarcinoma is a stroma-rich and highly challenging cancer to treat. Over recent years, it has become increasingly evident that the complex network of soluble cytokines, growth factors, proteases, and components of the extracellular matrix collaboratively interact within the tumor microenvironment, sustaining and driving cancer cell proliferation, invasion, and early metastasis. More recently, the tumor microenvironment has also been appreciated to mediate therapeutic resistance in pancreatic ductal adenocarcinoma, thus opening numerous avenues for novel therapeutic explorations. Inert and soluble components of the tumor stroma have been targeted in order to break down the extracellular matrix scaffold, relieve vessel compression, and increase drug delivery to hypovascular tumors. Moreover, targeting of antiapoptotic, immunosuppressive, and pro-proliferative effects of the tumor stroma provides novel vantage points of attack. This review focuses on current and future developments in pancreatic cancer medicine, with a particular emphasis on biophysical and biochemical approaches that target the tumor microenvironment.

13 Review The pancreas cancer microenvironment. 2012

Feig, Christine / Gopinathan, Aarthi / Neesse, Albrecht / Chan, Derek S / Cook, Natalie / Tuveson, David A. ·Cambridge Research Institute, Cancer Research UK. ·Clin Cancer Res · Pubmed #22896693.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDA) is a common and lethal malignancy resulting in more than 250,000 deaths per year worldwide. Despite extensive efforts, cytotoxic and targeted therapies have provided only limited efficacy for patients with PDA to date. One contributing factor to the failure of systemic therapies may be the abundant tumor stromal content that is the characteristic of PDA. The PDA stroma, aptly termed the tumor microenvironment, occupies the majority of the tumor mass, and consists of a dynamic assortment of extracellular matrix components and nonneoplastic cells including fibroblastic, vascular, and immune cells. Recent work has revealed that the PDA stroma supports tumor growth and promotes metastasis and simultaneously serves as a physical barrier to drug delivery. Accordingly, methods that alter stromal composition or function, for instance interference with the vasculature via Notch/Hedgehog pathway inhibition or relief of vascular compression by hyaluronidase, are under active investigation. Here, we will review our current understanding of the PDA tumor microenvironment, and highlight opportunities for further exploration that may benefit patients.

14 Review What we have learned about pancreatic cancer from mouse models. 2012

Pérez-Mancera, Pedro A / Guerra, Carmen / Barbacid, Mariano / Tuveson, David A. ·Li Ka Shing Centre, Cambridge Research Institute, and Department of Oncology, Cancer Research UK, Cambridge, England. ·Gastroenterology · Pubmed #22406637.

ABSTRACT: -- No abstract --

15 Review Stromal biology and therapy in pancreatic cancer. 2011

Neesse, Albrecht / Michl, Patrick / Frese, Kristopher K / Feig, Christine / Cook, Natalie / Jacobetz, Mike A / Lolkema, Martijn P / Buchholz, Malte / Olive, Kenneth P / Gress, Thomas M / Tuveson, David A. ·Li Ka Shing Centre, Cambridge Research Institute, Cancer Research UK, Cambridge, UK. ·Gut · Pubmed #20966025.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDA) is an almost uniformly lethal disease. One explanation for the devastating prognosis is the failure of many chemotherapies, including the current standard of care therapy gemcitabine. Although our knowledge of the molecular events underlying multistep carcinogenesis in PDA has steadily increased, translation into more effective therapeutic approaches has been inefficient over the last several decades. Evidence for this innate resistance to systemic therapies was recently provided in an accurate mouse model of PDA by the demonstration that chemotherapies are poorly delivered to PDA tissues because of a deficient vasculature. This vascular deficiency correlated with the presence of a dense stromal matrix that is a prominent histological hallmark of PDA tumours. Therapeutic targeting of stromal cells decreased the stroma from pancreatic tumours, resulting in increased intratumoral perfusion and therapeutic delivery of gemcitabine. Stromal cells contained within the PDA tumour microenvironment therefore represent an additional constituent to neoplastic cells that should be critically evaluated for optimal therapeutic development in preclinical models and early clinical trials.

16 Review Deploying mouse models of pancreatic cancer for chemoprevention studies. 2010

Grippo, Paul J / Tuveson, David A. ·Robert H Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, 303 East Superior Street, Chicago, IL 60611, USA. p-grippo@northwestern.edu ·Cancer Prev Res (Phila) · Pubmed #21045161.

ABSTRACT: With the advent of mouse models that recapitulate the cellular and molecular pathology of pancreatic neoplasia and cancer, it is now feasible to recruit and deploy these models for the evaluation of various chemopreventive and/or anticancer regimens. The highly lethal nature of pancreatic ductal adenocarcinoma (PDAC) makes multiple areas of research a priority, including assessment of compounds that prevent or suppress the development of early lesions that can transform into PDAC. Currently, there are over a dozen models available, which range from homogeneous preneoplastic lesions with remarkable similarity to human pancreatic intraepithelial neoplasms to models with a more heterogeneous population of lesions including cystic papillary and mucinous lesions. The molecular features of these models may also vary in a manner comparable with the differences observed in lesion morphology, and so, navigating the route of model selection is not trivial. Yet, arming the community of cancer investigators with a repertoire of models and the guidance to select relevant models that fit their research themes promises to produce findings that will have clinical relevance.

17 Clinical Trial A phase I trial of the γ-secretase inhibitor MK-0752 in combination with gemcitabine in patients with pancreatic ductal adenocarcinoma. 2018

Cook, Natalie / Basu, Bristi / Smith, Donna-Michelle / Gopinathan, Aarthi / Evans, Jeffry / Steward, William P / Palmer, Daniel / Propper, David / Venugopal, Balaji / Hategan, Mirela / Anthoney, D Alan / Hampson, Lisa V / Nebozhyn, Michael / Tuveson, David / Farmer-Hall, Hayley / Turner, Helen / McLeod, Robert / Halford, Sarah / Jodrell, Duncan. ·Cancer Research UK, Cambridge Research Institute, University of Cambridge Robinson Way, Cambridge CB2 0RE, UK. · Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0RE, UK. · Beatson West of Scotland Cancer Centre, University of Glasgow, Glasgow G12 0YN, United Kingdom. · Department of Oncology, University of Leicester, Leicester LE2 7LX, UK. · Clatterbridge Cancer Centre, Clatterbridge Road, Bebington, Wirral CH63 4JY, UK. · Bart's Cancer Institute, Queen Mary University of London EC1M 6BQ, London, UK. · Cancer Research UK, Centre for Drug Development, Angel Building, 407 St. John Street, London EC1V 4AD, UK. · St James Institute of Oncology, University of Leeds & Leeds Teaching Hospitals Trust, Leeds LS9 7TF, UK. · Department of Mathematics and Statistics, Fylde College, Lancaster University, Lancaster LA1 4YF, UK. · Merck & Co., Inc., Kenilworth, NJ 07033, USA. · Cold Spring Harbor Laboratories, Cold Spring Harbor, NY 11724, USA. ·Br J Cancer · Pubmed #29438372.

ABSTRACT: BACKGROUND: The Notch pathway is frequently activated in cancer. Pathway inhibition by γ-secretase inhibitors has been shown to be effective in pre-clinical models of pancreatic cancer, in combination with gemcitabine. METHODS: A multi-centre, non-randomised Bayesian adaptive design study of MK-0752, administered per os weekly, in combination with gemcitabine administered intravenously on days 1, 8 and 15 (28 day cycle) at 800 or 1000 mg m RESULTS: Overall, 44 eligible patients (performance status 0 or 1 with adequate organ function) received gemcitabine and MK-0752 as first or second line treatment for pancreatic cancer. RP2Ds of MK-0752 and gemcitabine as single agents could be combined safely. The Bayesian algorithm allowed further dose escalation, but pharmacokinetic analysis showed no increase in MK-0752 AUC (area under the curve) beyond 1800 mg once weekly. Tumour response evaluation was available in 19 patients; 13 achieved stable disease and 1 patient achieved a confirmed partial response. CONCLUSIONS: Gemcitabine and a γ-secretase inhibitor (MK-0752) can be combined at their full, single-agent RP2Ds.

18 Article Glutamine Anabolism Plays a Critical Role in Pancreatic Cancer by Coupling Carbon and Nitrogen Metabolism. 2019

Bott, Alex J / Shen, Jianliang / Tonelli, Claudia / Zhan, Le / Sivaram, Nithya / Jiang, Ya-Ping / Yu, Xufen / Bhatt, Vrushank / Chiles, Eric / Zhong, Hua / Maimouni, Sara / Dai, Weiwei / Velasquez, Stephani / Pan, Ji-An / Muthalagu, Nathiya / Morton, Jennifer / Anthony, Tracy G / Feng, Hui / Lamers, Wouter H / Murphy, Daniel J / Guo, Jessie Yanxiang / Jin, Jian / Crawford, Howard C / Zhang, Lanjing / White, Eileen / Lin, Richard Z / Su, Xiaoyang / Tuveson, David A / Zong, Wei-Xing. ·Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, USA; Genetics Graduate Program, Stony Brook University, Stony Brook, NY 07794, USA. · Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, USA. · Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA. · Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08901, USA. · Department of Physiology and Biophysics, Stony Brook University, Stony Brook, NY 11794, USA; Northport VA Medical Center, Northport, NY 11768, USA. · Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. · Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08901, USA; Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA. · CRUK Beatson Institute, Glasgow G61 1BD, UK. · Department of Nutritional Sciences, Rutgers University, New Brunswick, NJ 08901, USA. · Departments of Pharmacology and Medicine, Section of Hematology and Medical Oncology, Cancer Research Center, Boston University School of Medicine, Boston, MA 02118, USA. · Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands. · CRUK Beatson Institute, Glasgow G61 1BD, UK; Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1BD, UK. · Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, USA; Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08901, USA; Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA. · Departments of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA. · Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, USA; Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08901, USA; Department of Biological Sciences, Rutgers University, Newark, NJ 07102, USA. · Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, USA; Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08901, USA. Electronic address: zongwx@rutgers.edu. ·Cell Rep · Pubmed #31665640.

ABSTRACT: Glutamine is thought to play an important role in cancer cells by being deaminated via glutaminolysis to α-ketoglutarate (aKG) to fuel the tricarboxylic acid (TCA) cycle. Supporting this notion, aKG supplementation can restore growth/survival of glutamine-deprived cells. However, pancreatic cancers are often poorly vascularized and limited in glutamine supply, in alignment with recent concerns on the significance of glutaminolysis in pancreatic cancer. Here, we show that aKG-mediated rescue of glutamine-deprived pancreatic ductal carcinoma (PDAC) cells requires glutamate ammonia ligase (GLUL), the enzyme responsible for de novo glutamine synthesis. GLUL-deficient PDAC cells are capable of the TCA cycle but defective in aKG-coupled glutamine biosynthesis and subsequent nitrogen anabolic processes. Importantly, GLUL expression is elevated in pancreatic cancer patient samples and in mouse PDAC models. GLUL ablation suppresses the development of Kras

19 Article A FATal Combination: Fibroblast-Derived Lipids and Cancer-Derived Autotaxin Promote Pancreatic Cancer Growth. 2019

Biffi, Giulia / Tuveson, David A. ·Cold Spring Harbor Laboratory, Cold Spring Harbor, New York. dtuveson@cshl.edu gbiffi@cshl.edu. · Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, New York. ·Cancer Discov · Pubmed #31043410.

ABSTRACT: In this issue of

20 Article Generation and Culture of Tumor and Metastatic Organoids from Murine Models of Pancreatic Ductal Adenocarcinoma. 2019

Baker, Lindsey A / Tuveson, David A. ·Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA. lbaker@cshl.edu. · Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY, USA. lbaker@cshl.edu. · Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA. dtuveson@cshl.edu. · Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY, USA. dtuveson@cshl.edu. ·Methods Mol Biol · Pubmed #30378048.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy that is refractory to all current therapies. Research into the mechanisms driving this cancer is the key to developing better diagnostic and treatment options which are urgently needed in the clinic. Genetically engineered mouse models of PDA have been valuable research tools, enabling studies of all stages of PDA progression. However, these models are difficult and time-consuming to breed, and engineering further mutations into these models requires additional time. Recently, organoid cultures of PDA have emerged as alternative models for this disease. Organoids can be rapidly generated from mouse models of PDA and enable genetic and biochemical perturbation of all stages of PDA progression. Here, we describe the generation and propagation of organoid models from PDA tumors and metastases harvested from genetically engineered mouse models.

21 Article Generation and Culture of Human Pancreatic Ductal Adenocarcinoma Organoids from Resected Tumor Specimens. 2019

Baker, Lindsey A / Tiriac, Hervé / Tuveson, David A. ·Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA. lbaker@cshl.edu. · Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY, USA. lbaker@cshl.edu. · Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA. · Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY, USA. · Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA. dtuveson@cshl.edu. · Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY, USA. dtuveson@cshl.edu. ·Methods Mol Biol · Pubmed #30378047.

ABSTRACT: The recent development of human organoids as patient-specific models of pancreatic ductal adenocarcinoma (PDA) has helped set the stage for a new era of personalized medicine. Organoids can be generated from a resected PDA tumor in as little as 2-4 weeks, and are amenable to therapeutic screening as well as genetic and biochemical perturbation. Moreover, because these models promote the propagation of the neoplastic PDA cells at the expense of the stromal cells, transcriptome and genome-wide sequencing of organoids offers an unprecedented view of the genetic and expression changes occurring in the neoplastic cells of individual tumors. Here, we describe methods to generate PDA organoid cultures from resected human tumor specimens. We also describe how to propagate, cryopreserve, and thaw human PDA organoid cultures.

22 Article TP63-Mediated Enhancer Reprogramming Drives the Squamous Subtype of Pancreatic Ductal Adenocarcinoma. 2018

Somerville, Tim D D / Xu, Yali / Miyabayashi, Koji / Tiriac, Hervé / Cleary, Cristian R / Maia-Silva, Diogo / Milazzo, Joseph P / 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. · Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Graduate Program in Genetics, Stony Brook University, Stony Brook, NY 11794, USA. · Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA. · Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA. Electronic address: vakoc@cshl.edu. ·Cell Rep · Pubmed #30428345.

ABSTRACT: The aberrant expression of squamous lineage markers in pancreatic ductal adenocarcinoma (PDA) has been correlated with poor clinical outcomes. However, the functional role of this putative transdifferentiation event in PDA pathogenesis remains unclear. Here, we show that expression of the transcription factor TP63 (ΔNp63) is sufficient to install and sustain the enhancer landscape and transcriptional signature of the squamous lineage in human PDA cells. We also demonstrate that TP63-driven enhancer reprogramming promotes aggressive tumor phenotypes, including enhanced cell motility and invasion, and an accelerated growth of primary PDA tumors and metastases in vivo. This process ultimately leads to a powerful addiction of squamous PDA cells to continuous TP63 expression. Our study demonstrates the functional significance of squamous transdifferentiation in PDA and reveals TP63-based reprogramming as an experimental tool for investigating mechanisms and vulnerabilities linked to this aberrant cell fate transition.

23 Article Real-time Genomic Characterization of Advanced Pancreatic Cancer to Enable Precision Medicine. 2018

Aguirre, Andrew J / Nowak, Jonathan A / Camarda, Nicholas D / Moffitt, Richard A / Ghazani, Arezou A / Hazar-Rethinam, Mehlika / Raghavan, Srivatsan / Kim, Jaegil / Brais, Lauren K / Ragon, Dorisanne / Welch, Marisa W / Reilly, Emma / McCabe, Devin / Marini, Lori / Anderka, Kristin / Helvie, Karla / Oliver, Nelly / Babic, Ana / Da Silva, Annacarolina / Nadres, Brandon / Van Seventer, Emily E / Shahzade, Heather A / St Pierre, Joseph P / Burke, Kelly P / Clancy, Thomas / Cleary, James M / Doyle, Leona A / Jajoo, Kunal / McCleary, Nadine J / Meyerhardt, Jeffrey A / Murphy, Janet E / Ng, Kimmie / Patel, Anuj K / Perez, Kimberly / Rosenthal, Michael H / Rubinson, Douglas A / Ryou, Marvin / Shapiro, Geoffrey I / Sicinska, Ewa / Silverman, Stuart G / Nagy, Rebecca J / Lanman, Richard B / Knoerzer, Deborah / Welsch, Dean J / Yurgelun, Matthew B / Fuchs, Charles S / Garraway, Levi A / Getz, Gad / Hornick, Jason L / Johnson, Bruce E / Kulke, Matthew H / Mayer, Robert J / Miller, Jeffrey W / Shyn, Paul B / Tuveson, David A / Wagle, Nikhil / Yeh, Jen Jen / Hahn, William C / Corcoran, Ryan B / Carter, Scott L / Wolpin, Brian M. ·Dana-Farber Cancer Institute, Boston, Massachusetts. andrew_aguirre@dfci.harvard.edu carter.scott@jimmy.harvard.edu brian_wolpin@dfci.harvard.edu. · Broad Institute of Harvard and MIT, Cambridge, Massachusetts. · Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts. · Harvard Medical School, Boston, Massachusetts. · Dana-Farber Cancer Institute, Boston, Massachusetts. · Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts. · Joint Center for Cancer Precision Medicine, Dana-Farber Cancer Institute/Brigham and Women's Hospital, Boston, Massachusetts. · Harvard T.H. Chan School of Public Health, Boston, Massachusetts. · Department of Biomedical Informatics, Department of Pathology, Stony Brook University, Stony Brook, New York. · Massachusetts General Hospital Cancer Center, Boston, Massachusetts. · Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts. · Department of Gastroenterology, Brigham and Women's Hospital, Boston, Massachusetts. · Department of Radiology, Brigham and Women's Hospital, Boston, Massachusetts. · Department of Medical Affairs, Guardant Health, Inc., Redwood City, California. · BioMed Valley Discoveries, Kansas City, Missouri. · Cold Spring Harbor Laboratory, Cold Spring Harbor, New York; Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, New York. · Departments of Surgery and Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina. ·Cancer Discov · Pubmed #29903880.

ABSTRACT: Clinically relevant subtypes exist for pancreatic ductal adenocarcinoma (PDAC), but molecular characterization is not yet standard in clinical care. We implemented a biopsy protocol to perform time-sensitive whole-exome sequencing and RNA sequencing for patients with advanced PDAC. Therapeutically relevant genomic alterations were identified in 48% (34/71) and pathogenic/likely pathogenic germline alterations in 18% (13/71) of patients. Overall, 30% (21/71) of enrolled patients experienced a change in clinical management as a result of genomic data. Twenty-six patients had germline and/or somatic alterations in DNA-damage repair genes, and 5 additional patients had mutational signatures of homologous recombination deficiency but no identified causal genomic alteration. Two patients had oncogenic in-frame

24 Article Organoid Profiling Identifies Common Responders to Chemotherapy in Pancreatic Cancer. 2018

Tiriac, Hervé / Belleau, Pascal / Engle, Dannielle D / Plenker, Dennis / Deschênes, Astrid / Somerville, Tim D D / Froeling, Fieke E M / Burkhart, Richard A / Denroche, Robert E / Jang, Gun-Ho / Miyabayashi, Koji / Young, C Megan / Patel, Hardik / Ma, Michelle / LaComb, Joseph F / Palmaira, Randze Lerie D / Javed, Ammar A / Huynh, Jasmine C / Johnson, Molly / Arora, Kanika / Robine, Nicolas / Shah, Minita / Sanghvi, Rashesh / Goetz, Austin B / Lowder, Cinthya Y / Martello, Laura / Driehuis, Else / LeComte, Nicolas / Askan, Gokce / Iacobuzio-Donahue, Christine A / Clevers, Hans / Wood, Laura D / Hruban, Ralph H / Thompson, Elizabeth / Aguirre, Andrew J / Wolpin, Brian M / Sasson, Aaron / Kim, Joseph / Wu, Maoxin / Bucobo, Juan Carlos / Allen, Peter / Sejpal, Divyesh V / Nealon, William / Sullivan, James D / Winter, Jordan M / Gimotty, Phyllis A / Grem, Jean L / DiMaio, Dominick J / Buscaglia, Jonathan M / Grandgenett, Paul M / Brody, Jonathan R / Hollingsworth, Michael A / O'Kane, Grainne M / Notta, Faiyaz / Kim, Edward / Crawford, James M / Devoe, Craig / Ocean, Allyson / Wolfgang, Christopher L / Yu, Kenneth H / Li, Ellen / Vakoc, Christopher R / Hubert, Benjamin / Fischer, Sandra E / Wilson, Julie M / Moffitt, Richard / Knox, Jennifer / Krasnitz, Alexander / Gallinger, Steven / Tuveson, David A. ·Cold Spring Harbor Laboratory, Cold Spring Harbor, New York. · Johns Hopkins University, Division of Hepatobiliary and Pancreatic Surgery, Baltimore, Maryland. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada. · Swiss Federal Institute of Technology Lausanne (EPFL), School of Life Sciences, Swiss Institute for Experimental Cancer Research (ISREC), Laboratory of Tumor Heterogeneity and Stemness in Cancer, Lausanne, Switzerland. · Department of Medicine, Stony Brook University, Stony Brook, New York. · Memorial Sloan Kettering Cancer Center, New York, New York. · University of California, Davis, Comprehensive Cancer Center, Division of Hematology and Oncology, Sacramento, California. · New York Genome Center, New York, New York. · Department of Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania. · SUNY Downstate Medical Center, Department of Medicine, New York, New York. · Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW), Utrecht, the Netherlands. · University Medical Center (UMC), Utrecht, the Netherlands. · Princess Maxime Center (PMC), Utrecht, the Netherlands. · Department of Pathology, Johns Hopkins University, Baltimore, Maryland. · Dana-Farber Cancer Institute, Broad Institute, Boston, Massachusetts. · Department of Surgery, Stony Brook University, Stony Brook, New York. · Department of Pathology, Stony Brook University, Stony Brook, New York. · Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Division of Gastroenterology, Hempstead, New York. · Department of Surgery, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York. · Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, Pennsylvania. · Department of Medicine, University of Nebraska Medical Center, Omaha, Nebraska. · Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska. · University of Nebraska Medical Center, Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffet Cancer Center, Omaha, Nebraska. · Wallace McCain Centre for Pancreatic Cancer, Department of Medical Oncology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada. · Department of Pathology and Laboratory Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York. · Division of Medical Oncology, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York. · Weill Cornell Medical College, New York, New York. · Department of Pathology, University Health Network, University of Toronto, Toronto, Ontario, Canada. · Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. · Department of Biomedical Informatics, Stony Brook University, Stony Brook, New York. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada. dtuveson@cshl.edu steven.gallinger@uhn.ca. · Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. · Hepatobiliary/Pancreatic Surgical Oncology Program, University Health Network, Toronto, Ontario, Canada. · Cold Spring Harbor Laboratory, Cold Spring Harbor, New York. dtuveson@cshl.edu steven.gallinger@uhn.ca. ·Cancer Discov · Pubmed #29853643.

ABSTRACT: Pancreatic cancer is the most lethal common solid malignancy. Systemic therapies are often ineffective, and predictive biomarkers to guide treatment are urgently needed. We generated a pancreatic cancer patient-derived organoid (PDO) library that recapitulates the mutational spectrum and transcriptional subtypes of primary pancreatic cancer. New driver oncogenes were nominated and transcriptomic analyses revealed unique clusters. PDOs exhibited heterogeneous responses to standard-of-care chemotherapeutics and investigational agents. In a case study manner, we found that PDO therapeutic profiles paralleled patient outcomes and that PDOs enabled longitudinal assessment of chemosensitivity and evaluation of synchronous metastases. We derived organoid-based gene expression signatures of chemosensitivity that predicted improved responses for many patients to chemotherapy in both the adjuvant and advanced disease settings. Finally, we nominated alternative treatment strategies for chemorefractory PDOs using targeted agent therapeutic profiling. We propose that combined molecular and therapeutic profiling of PDOs may predict clinical response and enable prospective therapeutic selection.

25 Article Macrophage-Derived Granulin Drives Resistance to Immune Checkpoint Inhibition in Metastatic Pancreatic Cancer. 2018

Quaranta, Valeria / Rainer, Carolyn / Nielsen, Sebastian R / Raymant, Meirion L / Ahmed, Muhammad S / Engle, Dannielle D / Taylor, Arthur / Murray, Trish / Campbell, Fiona / Palmer, Daniel H / Tuveson, David A / Mielgo, Ainhoa / Schmid, Michael C. ·Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom. · Cold Spring Harbor Laboratory, Cold Spring Harbor, New York. · Department of Cellular and Molecular Physiology, University of Liverpool, Liverpool, United Kingdom. · Lustgarten Pancreatic Cancer Research Laboratory, Cold Spring Harbor, New York. · Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom. mschmid@liverpool.ac.uk. ·Cancer Res · Pubmed #29789416.

ABSTRACT: The ability of disseminated cancer cells to evade the immune response is a critical step for efficient metastatic progression. Protection against an immune attack is often provided by the tumor microenvironment that suppresses and excludes cytotoxic CD8

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