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Pancreatic Neoplasms: HELP
Articles by Nilotpal Roy
Based on 9 articles published since 2010
(Why 9 articles?)
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Between 2010 and 2020, Nilotpal Roy wrote the following 9 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Review Regulation of Cellular Identity in Cancer. 2015

Roy, Nilotpal / Hebrok, Matthias. ·Diabetes Center, Department of Medicine, University of California, San Francisco, CA 94143, USA. · Diabetes Center, Department of Medicine, University of California, San Francisco, CA 94143, USA. Electronic address: mhebrok@diabetes.ucsf.edu. ·Dev Cell · Pubmed #26702828.

ABSTRACT: Neoplastic transformation requires changes in cellular identity. Emerging evidence increasingly points to cellular reprogramming, a process during which fully differentiated and functional cells lose aspects of their identity while gaining progenitor characteristics, as a critical early step during cancer initiation. This cell identity crisis persists even at the malignant stage in certain cancers, suggesting that reactivation of progenitor functions supports tumorigenicity. Here, we review recent findings that establish the essential role of cellular reprogramming during neoplastic transformation and the major players involved in it with a special emphasis on pancreatic cancer.

2 Article The BRG1/SOX9 axis is critical for acinar cell-derived pancreatic tumorigenesis. 2018

Tsuda, Motoyuki / Fukuda, Akihisa / Roy, Nilotpal / Hiramatsu, Yukiko / Leonhardt, Laura / Kakiuchi, Nobuyuki / Hoyer, Kaja / Ogawa, Satoshi / Goto, Norihiro / Ikuta, Kozo / Kimura, Yoshito / Matsumoto, Yoshihide / Takada, Yutaka / Yoshioka, Takuto / Maruno, Takahisa / Yamaga, Yuichi / Kim, Grace E / Akiyama, Haruhiko / Ogawa, Seishi / Wright, Christopher V / Saur, Dieter / Takaori, Kyoichi / Uemoto, Shinji / Hebrok, Matthias / Chiba, Tsutomu / Seno, Hiroshi. ·Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan. · Diabetes Center, Department of Medicine, UCSF, San Francisco, California, USA. · Department of Pathology and Tumor Biology, Kyoto University Graduate School of Medicine, Kyoto, Japan. · Hematology, Oncology and Tumorimmunology, Charite-Universitätsmedizin Berlin, Berlin, Germany. · Department of Pathology, UCSF, San Francisco, California, USA. · Department of Orthopaedics, Gifu University, Gifu, Japan. · Program in Developmental Biology and Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA. · Department of Internal Medicine II, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany. · Division of Hepatobiliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan. · Kansai Electric Power Hospital, Osaka, Japan. ·J Clin Invest · Pubmed #30010625.

ABSTRACT: Chromatin remodeler Brahma related gene 1 (BRG1) is silenced in approximately 10% of human pancreatic ductal adenocarcinomas (PDAs). We previously showed that BRG1 inhibits the formation of intraductal pancreatic mucinous neoplasm (IPMN) and that IPMN-derived PDA originated from ductal cells. However, the role of BRG1 in pancreatic intraepithelial neoplasia-derived (PanIN-derived) PDA that originated from acinar cells remains elusive. Here, we found that exclusive elimination of Brg1 in acinar cells of Ptf1a-CreER; KrasG12D; Brg1fl/fl mice impaired the formation of acinar-to-ductal metaplasia (ADM) and PanIN independently of p53 mutation, while PDA formation was inhibited in the presence of p53 mutation. BRG1 bound to regions of the Sox9 promoter to regulate its expression and was critical for recruitment of upstream regulators, including PDX1, to the Sox9 promoter and enhancer in acinar cells. SOX9 expression was downregulated in BRG1-depleted ADMs/PanINs. Notably, Sox9 overexpression canceled this PanIN-attenuated phenotype in KBC mice. Furthermore, Brg1 deletion in established PanIN by using a dual recombinase system resulted in regression of the lesions in mice. Finally, BRG1 expression correlated with SOX9 expression in human PDAs. In summary, BRG1 is critical for PanIN initiation and progression through positive regulation of SOX9. Thus, the BRG1/SOX9 axis is a potential target for PanIN-derived PDA.

3 Article Atypical flat lesions derive from pancreatic acinar cells. 2017

von Figura, Guido / Fahrenkrog-Petersen, Leonie / Hidalgo-Sastre, Ana / Hartmann, Daniel / Hüser, Norbert / Schmid, Roland M / Hebrok, Matthias / Roy, Nilotpal / Esposito, Irene. ·II Medizinische Klinik und Poliklinik, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany. Electronic address: gvfigura@tum.de. · II Medizinische Klinik und Poliklinik, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany. · Chirurgische Klinik und Poliklinik, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany. · Diabetes Center, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA. · Institute of Pathology, University Clinic Duesseldorf, Heinrich-Heine University, Duesseldorf, Germany. ·Pancreatology · Pubmed #28473229.

ABSTRACT: OBJECTIVES: Pancreatic ductal adenocarcinoma (PDAC) is thought to derive from different precursor lesions including the recently identified atypical flat lesions (AFL). While all precursor lesions and PDAC share ductal characteristics, there is an ongoing debate about the cellular origin of the different PDAC precursor lesions. In particular, pancreatic acinar cells have previously been shown to display a remarkable plasticity being able to undergo ductal dedifferentiation in the context of oncogenic stimuli. METHODS: Histological analyses were performed in a murine PDAC model that specifically expresses oncogenic Kras in adult pancreatic acinar cells. Occurrence, characterization, and lineage tracing of AFLs were investigated. RESULTS: Upon expression of oncogenic Kras in adult pancreatic acinar cells, AFLs with typical morphology and expression profile arise. Lineage tracing confirmed that the AFLs were of acinar origin. CONCLUSIONS: Using a murine PDAC model, this study identifies pancreatic acinar cells as a cellular source for AFLs.

4 Article Global Protease Activity Profiling Provides Differential Diagnosis of Pancreatic Cysts. 2017

Ivry, Sam L / Sharib, Jeremy M / Dominguez, Dana A / Roy, Nilotpal / Hatcher, Stacy E / Yip-Schneider, Michele T / Schmidt, C Max / Brand, Randall E / Park, Walter G / Hebrok, Matthias / Kim, Grace E / O'Donoghue, Anthony J / Kirkwood, Kimberly S / Craik, Charles S. ·Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California. · Pharmaceutical Sciences and Pharmacogenomics Graduate Program, University of California, San Francisco, San Francisco, California. · Department of Surgery, University of California, San Francisco, San Francisco, California. · Diabetes Center, Department of Medicine, University of California, San Francisco, San Francisco, California. · Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana. · Division of Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. · Department of Medicine, Stanford University School of Medicine, Stanford, California. · Department of Pathology, University of California, San Francisco, San Francisco, California. · Skaggs School of Pharmacy and Pharmaceutical Chemistry, University of California, San Diego, La Jolla, California. · Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California. Charles.Craik@ucsf.edu. ·Clin Cancer Res · Pubmed #28424202.

ABSTRACT:

5 Article PDX1 dynamically regulates pancreatic ductal adenocarcinoma initiation and maintenance. 2016

Roy, Nilotpal / Takeuchi, Kenneth K / Ruggeri, Jeanine M / Bailey, Peter / Chang, David / Li, Joey / Leonhardt, Laura / Puri, Sapna / Hoffman, Megan T / Gao, Shan / Halbrook, Christopher J / Song, Yan / Ljungman, Mats / Malik, Shivani / Wright, Christopher V E / Dawson, David W / Biankin, Andrew V / Hebrok, Matthias / Crawford, Howard C. ·Diabetes Center, Department of Medicine, University of California at San Francisco, San Francisco, California 94143, USA. · Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109, USA. · Wolfson Wohl Cancer Research Center, University of Glasgow, Glasgow G61 1BD, Scotland. · Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York 11794, USA. · Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan 48109, USA. · Department of Medicine/ Hematology and Oncology, University of California at San Francisco, San Francisco, California 94143, USA. · Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee 37240, USA. · Department of Pathology and Laboratory Medicine, University of California at Los Angeles, Los Angeles, California 90095, USA. ·Genes Dev · Pubmed #28087712.

ABSTRACT: Aberrant activation of embryonic signaling pathways is frequent in pancreatic ductal adenocarcinoma (PDA), making developmental regulators therapeutically attractive. Here we demonstrate diverse functions for pancreatic and duodenal homeobox 1 (PDX1), a transcription factor indispensable for pancreas development, in the progression from normal exocrine cells to metastatic PDA. We identify a critical role for PDX1 in maintaining acinar cell identity, thus resisting the formation of pancreatic intraepithelial neoplasia (PanIN)-derived PDA. Upon neoplastic transformation, the role of PDX1 changes from tumor-suppressive to oncogenic. Interestingly, subsets of malignant cells lose PDX1 expression while undergoing epithelial-to-mesenchymal transition (EMT), and PDX1 loss is associated with poor outcome. This stage-specific functionality arises from profound shifts in PDX1 chromatin occupancy from acinar cells to PDA. In summary, we report distinct roles of PDX1 at different stages of PDA, suggesting that therapeutic approaches against this potential target need to account for its changing functions at different stages of carcinogenesis. These findings provide insight into the complexity of PDA pathogenesis and advocate a rigorous investigation of therapeutically tractable targets at distinct phases of PDA development and progression.

6 Article Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression. 2016

Laklai, Hanane / Miroshnikova, Yekaterina A / Pickup, Michael W / Collisson, Eric A / Kim, Grace E / Barrett, Alex S / Hill, Ryan C / Lakins, Johnathon N / Schlaepfer, David D / Mouw, Janna K / LeBleu, Valerie S / Roy, Nilotpal / Novitskiy, Sergey V / Johansen, Julia S / Poli, Valeria / Kalluri, Raghu / Iacobuzio-Donahue, Christine A / Wood, Laura D / Hebrok, Matthias / Hansen, Kirk / Moses, Harold L / Weaver, Valerie M. ·Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, California, USA. · Department of Medicine, University of California, San Francisco, San Francisco, California, USA. · Department of Pathology, University of California, San Francisco, San Francisco, California, USA. · Department of Biochemistry and Molecular Genetics, University of Colorado, Denver, Aurora, Colorado, USA. · Department of Reproductive Medicine, University of California, San Diego Moores Cancer Center, La Jolla, California, USA. · Department of Cancer Biology, Metastasis Research Center, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA. · Diabetes Center, Department of Medicine, University of California, San Francisco, San Francisco, California, USA. · Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA. · Department of Oncology, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark. · Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Turin, Turin, Italy. · 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. · Gastrointestinal and Liver Pathology Department, Johns Hopkins University, Baltimore, Maryland, USA. · Department of Anatomy, University of California, San Francisco, San Francisco, California, USA. · Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, USA. · Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, California, USA. · Helen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, USA. ·Nat Med · Pubmed #27089513.

ABSTRACT: Fibrosis compromises pancreatic ductal carcinoma (PDAC) treatment and contributes to patient mortality, yet antistromal therapies are controversial. We found that human PDACs with impaired epithelial transforming growth factor-β (TGF-β) signaling have high epithelial STAT3 activity and develop stiff, matricellular-enriched fibrosis associated with high epithelial tension and shorter patient survival. In several KRAS-driven mouse models, both the loss of TGF-β signaling and elevated β1-integrin mechanosignaling engaged a positive feedback loop whereby STAT3 signaling promotes tumor progression by increasing matricellular fibrosis and tissue tension. In contrast, epithelial STAT3 ablation attenuated tumor progression by reducing the stromal stiffening and epithelial contractility induced by loss of TGF-β signaling. In PDAC patient biopsies, higher matricellular protein and activated STAT3 were associated with SMAD4 mutation and shorter survival. The findings implicate epithelial tension and matricellular fibrosis in the aggressiveness of SMAD4 mutant pancreatic tumors and highlight STAT3 and mechanics as key drivers of this phenotype.

7 Article p120 Catenin Suppresses Basal Epithelial Cell Extrusion in Invasive Pancreatic Neoplasia. 2016

Hendley, Audrey M / Wang, Yue J / Polireddy, Kishore / Alsina, Janivette / Ahmed, Ishrat / Lafaro, Kelly J / Zhang, Hao / Roy, Nilotpal / Savidge, Samuel G / Cao, Yanna / Hebrok, Matthias / Maitra, Anirban / Reynolds, Albert B / Goggins, Michael / Younes, Mamoun / Iacobuzio-Donahue, Christine A / Leach, Steven D / Bailey, Jennifer M. ·Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland. The McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland. Division of Gastroenterology, Hepatology, and Nutrition, Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, Texas. · Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland. The McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Division of Gastroenterology, Hepatology, and Nutrition, Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, Texas. · Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland. · The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland. The David Rubenstein Pancreatic Cancer Research Center, Memorial Sloan Kettering Cancer Center, New York, New York. · Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland. · Diabetes Center, University of California, San Francisco, San Francisco, California. · Department of Surgery, The University of Texas Health Science Center at Houston, Houston, Texas. · Department of Pathology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland. The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. Departments of Pathology and Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee. · Department of Pathology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland. The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland. Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Pathology and Laboratory Medicine, University of Texas Medical School at Houston, Houston, Texas. · The David Rubenstein Pancreatic Cancer Research Center, Memorial Sloan Kettering Cancer Center, New York, New York. Department of Pathology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland. The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland. The McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland. The David Rubenstein Pancreatic Cancer Research Center, Memorial Sloan Kettering Cancer Center, New York, New York. leachs@mskcc.org Jennifer.M.Bailey@uth.tmc.edu. · Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland. The McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland. Division of Gastroenterology, Hepatology, and Nutrition, Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, Texas. leachs@mskcc.org Jennifer.M.Bailey@uth.tmc.edu. ·Cancer Res · Pubmed #27032419.

ABSTRACT: Aberrant regulation of cellular extrusion can promote invasion and metastasis. Here, we identify molecular requirements for early cellular invasion using a premalignant mouse model of pancreatic cancer with conditional knockout of p120 catenin (Ctnnd1). Mice with biallelic loss of p120 catenin progressively develop high-grade pancreatic intraepithelial neoplasia (PanIN) lesions and neoplasia accompanied by prominent acute and chronic inflammatory processes, which is mediated, in part, through NF-κB signaling. Loss of p120 catenin in the context of oncogenic Kras also promotes remarkable apical and basal epithelial cell extrusion. Abundant single epithelial cells exit PanIN epithelium basally, retain epithelial morphology, survive, and display features of malignancy. Similar extrusion defects are observed following p120 catenin knockdown in vitro, and these effects are completely abrogated by the activation of S1P/S1pr2 signaling. In the context of oncogenic Kras, p120 catenin loss significantly reduces expression of genes mediating S1P/S1pr2 signaling in vivo and in vitro, and this effect is mediated at least, in part, through activation of NF-κB. These results provide insight into mechanisms controlling early events in the metastatic process and suggest that p120 catenin and S1P/S1pr2 signaling enhance cancer progression by regulating epithelial cell invasion. Cancer Res; 76(11); 3351-63. ©2016 AACR.

8 Article Brg1 promotes both tumor-suppressive and oncogenic activities at distinct stages of pancreatic cancer formation. 2015

Roy, Nilotpal / Malik, Shivani / Villanueva, Karina E / Urano, Atsushi / Lu, Xinyuan / Von Figura, Guido / Seeley, E Scott / Dawson, David W / Collisson, Eric A / Hebrok, Matthias. ·Diabetes Center, Department of Medicine, University of California at San Francisco, San Francisco, California 94143, USA; · Department of Medicine/Hematology and Oncology, University of California at San Francisco, San Francisco, California 94143, USA; · II. Medizinische Klinik und Poliklinik, Klinikum Rechts der Isar der Technischen Universität München, 81675 Munich, Germany; · Department of Pathology, University of California at San Francisco, San Francisco, California 94143, USA; · Department of Pathology and Laboratory Medicine, University of California at Los Angeles, Los Angeles, California 90095, USA. · Diabetes Center, Department of Medicine, University of California at San Francisco, San Francisco, California 94143, USA; mhebrok@diabetes.ucsf.edu. ·Genes Dev · Pubmed #25792600.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDA) develops predominantly through pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasm (IPMN) precursor lesions. Pancreatic acinar cells are reprogrammed to a "ductal-like" state during PanIN-PDA formation. Here, we demonstrate a parallel mechanism operative in mature duct cells during which functional cells undergo "ductal retrogression" to form IPMN-PDA. We further identify critical antagonistic roles for Brahma-related gene 1 (Brg1), a catalytic subunit of the SWI/SNF complexes, during IPMN-PDA development. In mature duct cells, Brg1 inhibits the dedifferentiation that precedes neoplastic transformation, thus attenuating tumor initiation. In contrast, Brg1 promotes tumorigenesis in full-blown PDA by supporting a mesenchymal-like transcriptional landscape. We further show that JQ1, a drug that is currently being tested in clinical trials for hematological malignancies, impairs PDA tumorigenesis by both mimicking some and inhibiting other Brg1-mediated functions. In summary, our study demonstrates the context-dependent roles of Brg1 and points to potential therapeutic treatment options based on epigenetic regulation in PDA.

9 Article The chromatin regulator Brg1 suppresses formation of intraductal papillary mucinous neoplasm and pancreatic ductal adenocarcinoma. 2014

von Figura, Guido / Fukuda, Akihisa / Roy, Nilotpal / Liku, Muluye E / Morris Iv, John P / Kim, Grace E / Russ, Holger A / Firpo, Matthew A / Mulvihill, Sean J / Dawson, David W / Ferrer, Jorge / Mueller, William F / Busch, Anke / Hertel, Klemens J / Hebrok, Matthias. ·1] Diabetes Center, Department of Medicine, University of California, San Francisco, 513 Parnassus Avenue, HSW 1116, Box 0540 San Francisco, California 94143, USA [2] II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany [3]. · 1] Diabetes Center, Department of Medicine, University of California, San Francisco, 513 Parnassus Avenue, HSW 1116, Box 0540 San Francisco, California 94143, USA [2] Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan [3]. · 1] Diabetes Center, Department of Medicine, University of California, San Francisco, 513 Parnassus Avenue, HSW 1116, Box 0540 San Francisco, California 94143, USA [2]. · Diabetes Center, Department of Medicine, University of California, San Francisco, 513 Parnassus Avenue, HSW 1116, Box 0540 San Francisco, California 94143, USA. · Department of Pathology, University of California, San Francisco, San Francisco, California 94143, USA. · 1] Department of Surgery [2] Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84115, USA. · Department of Pathology, University of California, Los Angeles, California 90095, USA. · Department of Medicine, Imperial College London, W12 ONN London, UK. · Department of Microbiology & Molecular Genetics, University of California, Irvine, California 92697, USA. ·Nat Cell Biol · Pubmed #24561622.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDA) develops through distinct precursor lesions, including pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasia (IPMN). However, genetic features resulting in IPMN-associated PDA (IPMN-PDA) versus PanIN-associated PDA (PanIN-PDA) are largely unknown. Here we find that loss of Brg1, a core subunit of SWI/SNF chromatin remodelling complexes, cooperates with oncogenic Kras to form cystic neoplastic lesions that resemble human IPMN and progress to PDA. Although Brg1-null IPMN-PDA develops rapidly, it possesses a distinct transcriptional profile compared with PanIN-PDA driven by mutant Kras and hemizygous p53 deletion. IPMN-PDA also is less lethal, mirroring prognostic trends in PDA patients. In addition, Brg1 deletion inhibits Kras-dependent PanIN development from adult acinar cells, but promotes Kras-driven preneoplastic transformation in adult duct cells. Therefore, this study implicates Brg1 as a determinant of context-dependent Kras-driven pancreatic tumorigenesis and suggests that chromatin remodelling may underlie the development of distinct PDA subsets.