The acinar differentiation determinant PTF1A inhibits initiation of pancreatic ductal adenocarcinoma

Understanding the initiation and progression of pancreatic ductal adenocarcinoma (PDAC) may provide therapeutic strategies for this deadly disease. Recently, we and others made the surprising finding that PDAC and its preinvasive precursors, pancreatic intraepithelial neoplasia (PanIN), arise via reprogramming of mature acinar cells. We therefore hypothesized that the master regulator of acinar differentiation, PTF1A, could play a central role in suppressing PDAC initiation. In this study, we demonstrate that PTF1A expression is lost in both mouse and human PanINs, and that this downregulation is functionally imperative in mice for acinar reprogramming by oncogenic KRAS. Loss of Ptf1a alone is sufficient to induce acinar-to-ductal metaplasia, potentiate inflammation, and induce a KRAS-permissive, PDAC-like gene expression profile. As a result, Ptf1a-deficient acinar cells are dramatically sensitized to KRAS transformation, and reduced Ptf1a greatly accelerates development of invasive PDAC. Together, these data indicate that cell differentiation regulators constitute a new tumor suppressive mechanism in the pancreas. DOI: http://dx.doi.org/10.7554/eLife.07125.001

[1]  M. Korc,et al.  Pancreatic cancer-associated retinoblastoma 1 dysfunction enables TGF-β to promote proliferation. , 2016, The Journal of clinical investigation.

[2]  M. Keefe,et al.  Regeneration and repair of the exocrine pancreas. , 2015, Annual review of physiology.

[3]  M. Spector,et al.  Organoid Models of Human and Mouse Ductal Pancreatic Cancer , 2015, Cell.

[4]  H. Bien,et al.  PI3K regulation of RAC1 is required for KRAS-induced pancreatic tumorigenesis in mice. , 2014, Gastroenterology.

[5]  D. Saur,et al.  Pancreatic cell plasticity and cancer initiation induced by oncogenic Kras is completely dependent on wild-type PI 3-kinase p110α , 2014, Genes & development.

[6]  G. Wahl,et al.  Vitamin D Receptor-Mediated Stromal Reprogramming Suppresses Pancreatitis and Enhances Pancreatic Cancer Therapy , 2014, Cell.

[7]  A. Maitra,et al.  Oncogenic Kras activates a hematopoietic-to-epithelial IL-17 signaling axis in preinvasive pancreatic neoplasia. , 2014, Cancer cell.

[8]  A. Wellstein,et al.  Downstream of Mutant KRAS, the Transcription Regulator YAP Is Essential for Neoplastic Progression to Pancreatic Ductal Adenocarcinoma , 2014, Science Signaling.

[9]  Michael R. Green,et al.  A KRAS-directed transcriptional silencing pathway that mediates the CpG island methylator phenotype , 2014, eLife.

[10]  Muluye E. Liku,et al.  The chromatin regulator Brg1 suppresses formation of intraductal papillary mucinous neoplasm and pancreatic ductal adenocarcinoma , 2014, Nature Cell Biology.

[11]  J. Sebolt-Leopold,et al.  MAPK signaling is required for dedifferentiation of acinar cells and development of pancreatic intraepithelial neoplasia in mice. , 2014, Gastroenterology.

[12]  H. Crawford,et al.  The secret origins and surprising fates of pancreas tumors. , 2014, Carcinogenesis.

[13]  M. Korc,et al.  Pancreatic cancer-associated retinoblastoma 1 dysfunction enables TGF-β to promote proliferation. , 2014, The Journal of clinical investigation.

[14]  L. C. Murtaugh,et al.  Pathogenesis of Pancreatic Cancer , 2014, Toxicologic pathology.

[15]  Andreas Krämer,et al.  Causal analysis approaches in Ingenuity Pathway Analysis , 2013, Bioinform..

[16]  Anna Murray,et al.  Recessive mutations in a distal PTF1A enhancer cause isolated pancreatic agenesis , 2013, Nature Genetics.

[17]  Michael R. Green,et al.  Oncogenic RAS directs silencing of tumor suppressor genes through ordered recruitment of transcriptional repressors , 2013, Genes & development.

[18]  B. Necela,et al.  Macrophage-secreted cytokines drive pancreatic acinar-to-ductal metaplasia through NF-κB and MMPs , 2013, The Journal of cell biology.

[19]  Spencer G. Willet,et al.  Non‐parallel recombination limits cre‐loxP‐based reporters as precise indicators of conditional genetic manipulation , 2013, Genesis.

[20]  T. Wirth,et al.  Requirement of NEMO/IKKγ for effective expansion of KRAS-induced precancerous lesions in the pancreas , 2013, Oncogene.

[21]  C. Wright,et al.  Nr5a2 maintains acinar cell differentiation and constrains oncogenic Kras-mediated pancreatic neoplastic initiation , 2013, Gut.

[22]  M. Karin,et al.  Inflammation, autophagy, and obesity: common features in the pathogenesis of pancreatitis and pancreatic cancer. , 2013, Gastroenterology.

[23]  C. Logsdon,et al.  Roles for KRAS in pancreatic tumor development and progression. , 2013, Gastroenterology.

[24]  F. Real,et al.  Nr5a2 heterozygosity sensitises to, and cooperates with, inflammation in KRasG12V-driven pancreatic tumourigenesis , 2013, Gut.

[25]  C. Wright,et al.  Spatiotemporal patterns of multipotentiality in Ptf1a-expressing cells during pancreas organogenesis and injury-induced facultative restoration , 2013, Development.

[26]  C. Blanpain.  Tracing the cellular origin of cancer , 2013, Nature Cell Biology.

[27]  Huamin Wang,et al.  Activation of nuclear factor-κB in acinar cells increases the severity of pancreatitis in mice. , 2013, Gastroenterology.

[28]  Cole Trapnell,et al.  TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions , 2013, Genome Biology.

[29]  K. Jensen,et al.  Identification of Sox9-dependent acinar-to-ductal reprogramming as the principal mechanism for initiation of pancreatic ductal adenocarcinoma. , 2012, Cancer cell.

[30]  Jens T Siveke,et al.  EGF receptor is required for KRAS-induced pancreatic tumorigenesis. , 2012, Cancer cell.

[31]  M. Barbacid,et al.  EGF receptor signaling is essential for k-ras oncogene-driven pancreatic ductal adenocarcinoma. , 2012, Cancer cell.

[32]  Bond-Smith Giles,et al.  Only women with symptoms need to have their breast implants removed, says government , 2012 .

[33]  J. Mayerle,et al.  Tumour necrosis factor α secretion induces protease activation and acinar cell necrosis in acute experimental pancreatitis in mice , 2012, Gut.

[34]  Yan Liu,et al.  An NF-κB pathway-mediated positive feedback loop amplifies Ras activity to pathological levels in mice. , 2012, The Journal of clinical investigation.

[35]  J. J. Westmoreland,et al.  Dynamic distribution of claudin proteins in pancreatic epithelia undergoing morphogenesis or neoplastic transformation , 2012, Developmental dynamics : an official publication of the American Association of Anatomists.

[36]  C. Wright,et al.  Ongoing Notch signaling maintains phenotypic fidelity in the adult exocrine pancreas. , 2012, Developmental biology.

[37]  Maximilian Reichert,et al.  EMT and Dissemination Precede Pancreatic Tumor Formation , 2012, Cell.

[38]  M. Keefe,et al.  β-catenin is selectively required for the expansion and regeneration of mature pancreatic acinar cells in mice , 2012, Disease Models & Mechanisms.

[39]  D. Tuveson,et al.  Crosstalk between the canonical NF-κB and Notch signaling pathways inhibits Pparγ expression and promotes pancreatic cancer progression in mice. , 2011, The Journal of clinical investigation.

[40]  H. Friess,et al.  StellaTUM: current consensus and discussion on pancreatic stellate cell research , 2011, Gut.

[41]  A. Frey,et al.  Dendritic cells promote pancreatic viability in mice with acute pancreatitis. , 2011, Gastroenterology.

[42]  S. Kliewer,et al.  LRH-1 and PTF1-L coregulate an exocrine pancreas-specific transcriptional network for digestive function. , 2011, Genes & development.

[43]  P. Mazur,et al.  Early requirement of Rac1 in a mouse model of pancreatic cancer. , 2011, Gastroenterology.

[44]  F. Real,et al.  Pancreatic ductal adenocarcinoma and acinar cells: a matter of differentiation and development? , 2011, Gut.

[45]  P. Spellman,et al.  Subtypes of Pancreatic Ductal Adenocarcinoma and Their Differing Responses to Therapy , 2011, Nature Medicine.

[46]  M. Nowak,et al.  Distant Metastasis Occurs Late during the Genetic Evolution of Pancreatic Cancer , 2010, Nature.

[47]  T. Masui,et al.  Replacement of Rbpj with Rbpjl in the PTF1 complex controls the final maturation of pancreatic acinar cells. , 2010, Gastroenterology.

[48]  C. Paweletz,et al.  A gene expression signature of RAS pathway dependence predicts response to PI3K and RAS pathway inhibitors and expands the population of RAS pathway activated tumors , 2010, BMC Medical Genomics.

[49]  Sterling Thomas,et al.  A survey of current software for network analysis in molecular biology , 2010, Human Genomics.

[50]  Wei Zheng,et al.  A genome-wide association study identifies pancreatic cancer susceptibility loci on chromosomes 13q22.1, 1q32.1 and 5p15.33 , 2010, Nature Genetics.

[51]  Mark D. Robinson,et al.  edgeR: a Bioconductor package for differential expression analysis of digital gene expression data , 2009, Bioinform..

[52]  B. Pasche,et al.  Tgfbr1 haploinsufficiency inhibits the development of murine mutant Kras-induced pancreatic precancer. , 2009, Cancer research.

[53]  R. Hruban,et al.  Increased Prevalence of Precursor Lesions in Familial Pancreatic Cancer Patients , 2009, Clinical Cancer Research.

[54]  Huamin Wang,et al.  Ras activity levels control the development of pancreatic diseases. , 2009, Gastroenterology.

[55]  Patricia Greninger,et al.  A gene expression signature associated with "K-Ras addiction" reveals regulators of EMT and tumor cell survival. , 2009, Cancer cell.

[56]  R. Hruban,et al.  Loss of the acinar-restricted transcription factor Mist1 accelerates Kras-induced pancreatic intraepithelial neoplasia. , 2009, Gastroenterology.

[57]  A. Walch,et al.  Inflammation and mitochondrial fatty acid β-oxidation link obesity to early tumor promotion , 2009, Proceedings of the National Academy of Sciences.

[58]  J. L. Goodman,et al.  Notch and Kras reprogram pancreatic acinar cells to ductal intraepithelial neoplasia , 2008, Proceedings of the National Academy of Sciences.

[59]  G. Feldmann,et al.  Spontaneous induction of murine pancreatic intraepithelial neoplasia (mPanIN) by acinar cell targeting of oncogenic Kras in adult mice , 2008, Proceedings of the National Academy of Sciences.

[60]  T. Masui,et al.  Development and Adulthood Expression during Ptf1a Pancreatic Transcriptional Autoregulation Controls , 2008 .

[61]  Y. Dor,et al.  In vivo lineage tracing defines the role of acinar-to-ductal transdifferentiation in inflammatory ductal metaplasia. , 2007, Gastroenterology.

[62]  T. Masui,et al.  Early pancreatic development requires the vertebrate Suppressor of Hairless (RBPJ) in the PTF1 bHLH complex. , 2007, Genes & development.

[63]  Gerald C. Chu,et al.  Smad4 is dispensable for normal pancreas development yet critical in progression and tumor biology of pancreas cancer. , 2006, Genes & development.

[64]  J. Cameron,et al.  Multifocal Neoplastic Precursor Lesions Associated With Lobular Atrophy of the Pancreas in Patients Having a Strong Family History of Pancreatic Cancer , 2006, The American journal of surgical pathology.

[65]  Wolfgang Schima,et al.  Pancreatic adenocarcinoma , 2006, European Radiology.

[66]  Pablo Tamayo,et al.  Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[67]  S. Leach,et al.  Pancreatic epithelial plasticity mediated by acinar cell transdifferentiation and generation of nestin-positive intermediates , 2005, Development.

[68]  R. Hruban,et al.  Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. , 2005, Cancer cell.

[69]  E. Cameron,et al.  Recapitulation of elements of embryonic development in adult mouse pancreatic regeneration. , 2005, Gastroenterology.

[70]  A. Hattersley,et al.  Mutations in PTF1A cause pancreatic and cerebellar agenesis , 2004, Nature Genetics.

[71]  R. DePinho,et al.  Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma. , 2003, Genes & development.

[72]  E. Petricoin,et al.  Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. , 2003, Cancer cell.

[73]  A. McMahon,et al.  Maternal inheritance of Cre activity in a Sox2Cre deleter strain , 2003, Genesis.

[74]  C. Wright,et al.  The role of the transcriptional regulator Ptf1a in converting intestinal to pancreatic progenitors , 2002, Nature Genetics.

[75]  D. Melton,et al.  Direct evidence for the pancreatic lineage: NGN3+ cells are islet progenitors and are distinct from duct progenitors. , 2002, Development.

[76]  R. Bhonde,et al.  Analysis and optimization of nutritional set-up for murine pancreatic acinar cells. , 2002, JOP : Journal of the pancreas.

[77]  R. Hammer,et al.  The Role of PTF1-P48 in Pancreatic Acinar Gene Expression* , 2001, The Journal of Biological Chemistry.

[78]  S. F. Konieczny,et al.  The bHLH transcription factor Mist1 is required to maintain exocrine pancreas cell organization and acinar cell identity , 2001, The Journal of cell biology.

[79]  Shankar Srinivas,et al.  Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus , 2001, BMC Developmental Biology.

[80]  A. Berns,et al.  Induction of medulloblastomas in p53-null mutant mice by somatic inactivation of Rb in the external granular layer cells of the cerebellum. , 2000, Genes & development.

[81]  B. Neuschwander‐Tetri,et al.  Repetitive Acute Pancreatic Injury in the Mouse Induces Procollagen α1(I) Expression Colocalized to Pancreatic Stellate Cells , 2000, Laboratory Investigation.

[82]  A. Krapp,et al.  The bHLH protein PTF1-p48 is essential for the formation of the exocrine and the correct spatial organization of the endocrine pancreas. , 1998, Genes & development.

[83]  P. Lemaire,et al.  Community effects and related phenomena in development , 1993, Cell.

[84]  H. Harris.  The role of differentiation in the suppression of malignancy. , 1990, Journal of cell science.

[85]  J. Chirgwin,et al.  Isolation of RNA using guanidinium salts. , 1987, Methods in enzymology.

[86]  M. Anderson,et al.  Origin of tubular complexes in human chronic pancreatitis. , 1982, American journal of surgery.