Yap1 Activation Enables Bypass of Oncogenic Kras Addiction in Pancreatic Cancer

Activating mutations in KRAS are among the most frequent events in diverse human carcinomas and are particularly prominent in human pancreatic ductal adenocarcinoma (PDAC). An inducible Kras(G12D)-driven mouse model of PDAC has established a critical role for sustained Kras(G12D) expression in tumor maintenance, providing a model to determine the potential for and the underlying mechanisms of Kras(G12D)-independent PDAC recurrence. Here, we show that some tumors undergo spontaneous relapse and are devoid of Kras(G12D) expression and downstream canonical MAPK signaling and instead acquire amplification and overexpression of the transcriptional coactivator Yap1. Functional studies established the role of Yap1 and the transcriptional factor Tead2 in driving Kras(G12D)-independent tumor maintenance. The Yap1/Tead2 complex acts cooperatively with E2F transcription factors to activate a cell cycle and DNA replication program. Our studies, along with corroborating evidence from human PDAC models, portend a novel mechanism of escape from oncogenic Kras addiction in PDAC.

[1]  P. Northcott,et al.  YAP1 is amplified and up-regulated in hedgehog-associated medulloblastomas and mediates Sonic hedgehog-driven neural precursor proliferation. , 2009, Genes & development.

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

[3]  Anne E Carpenter,et al.  A Lentiviral RNAi Library for Human and Mouse Genes Applied to an Arrayed Viral High-Content Screen , 2006, Cell.

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

[5]  Martin Vingron,et al.  TransFind—predicting transcriptional regulators for gene sets , 2010, Nucleic Acids Res..

[6]  G. Parmigiani,et al.  Core Signaling Pathways in Human Pancreatic Cancers Revealed by Global Genomic Analyses , 2008, Science.

[7]  Li Li,et al.  Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control. , 2007, Genes & development.

[8]  S. Dry,et al.  PTEN loss accelerates KrasG12D-induced pancreatic cancer development. , 2010, Cancer research.

[9]  N. Jenkins,et al.  Response and Resistance to MEK Inhibition in Leukaemias Initiated by Hyperactive Ras , 2009, Nature.

[10]  C. Galbán,et al.  Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice. , 2012, The Journal of clinical investigation.

[11]  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.

[12]  D. Botstein,et al.  Cluster analysis and display of genome-wide expression patterns. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[13]  H. Sasaki,et al.  Mammalian Tead proteins regulate cell proliferation and contact inhibition as transcriptional mediators of Hippo signaling , 2008, Development.

[14]  I. Weinstein.  Addiction to Oncogenes--the Achilles Heal of Cancer , 2002, Science.

[15]  Joseph Rosenbluh,et al.  KRAS and YAP1 Converge to Regulate EMT and Tumor Survival , 2014, Cell.

[16]  Gerald C. Chu,et al.  P53 and Pten control neural and glioma stem/progenitor cell renewal and differentiation , 2008, Nature.

[17]  Jun O. Liu,et al.  Genetic and pharmacological disruption of the TEAD-YAP complex suppresses the oncogenic activity of YAP. , 2012, Genes & development.

[18]  Leah B. Honor,et al.  YAP1, the nuclear target of Hippo signaling, stimulates heart growth through cardiomyocyte proliferation but not hypertrophy , 2012, Proceedings of the National Academy of Sciences.

[19]  R. DePinho,et al.  Genetics and biology of pancreatic ductal adenocarcinoma. , 2006, Genes & development.

[20]  W. Kaelin,et al.  The cellular effects of E2F overexpression. , 1996, Current topics in microbiology and immunology.

[21]  O. Kirak,et al.  Yap1 Acts Downstream of α-Catenin to Control Epidermal Proliferation , 2011, Cell.

[22]  B. Stanger.  Quit your YAPing: a new target for cancer therapy. , 2012, Genes & development.

[23]  A. Pobbati,et al.  Emerging roles of TEAD transcription factors and its coactivators in cancers , 2013, Cancer biology & therapy.

[24]  Andrew Menzies,et al.  The patterns and dynamics of genomic instability in metastatic pancreatic cancer , 2010, Nature.

[25]  Alok J. Saldanha,et al.  Java Treeview - extensible visualization of microarray data , 2004, Bioinform..

[26]  L. Trusolino,et al.  Oncogene addiction as a foundational rationale for targeted anti-cancer therapy: promises and perils , 2011, EMBO molecular medicine.

[27]  J. Inazawa,et al.  YAP is a candidate oncogene for esophageal squamous cell carcinoma. , 2011, Carcinogenesis.

[28]  N. Sarvetnick,et al.  Hippo Signaling Regulates Pancreas Development through Inactivation of Yap , 2012, Molecular and Cellular Biology.

[29]  Jiandie D. Lin,et al.  TEAD mediates YAP-dependent gene induction and growth control. , 2008, Genes & development.

[30]  R. DePinho,et al.  Endogenous oncogenic K-ras(G12D) stimulates proliferation and widespread neoplastic and developmental defects. , 2004, Cancer cell.

[31]  Gerald C. Chu,et al.  Oncogenic Kras Maintains Pancreatic Tumors through Regulation of Anabolic Glucose Metabolism , 2012, Cell.

[32]  R. Bernards,et al.  Understanding resistance to targeted cancer drugs through loss of function genetic screens. , 2012, Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy.

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

[34]  A. Penzo-Méndez,et al.  Hippo signaling regulates differentiation and maintenance in the exocrine pancreas. , 2013, Gastroenterology.

[35]  Manuel Serrano,et al.  Tumor induction by an endogenous K-ras oncogene is highly dependent on cellular context. , 2003, Cancer cell.

[36]  E. Olson,et al.  Hippo pathway effector Yap promotes cardiac regeneration , 2013, Proceedings of the National Academy of Sciences.

[37]  D. Hanahan,et al.  Hallmarks of Cancer: The Next Generation , 2011, Cell.

[38]  C. Tamm,et al.  Regulation of mouse embryonic stem cell self-renewal by a Yes–YAP–TEAD2 signaling pathway downstream of LIF , 2011, Journal of Cell Science.

[39]  Gordon K Smyth,et al.  Statistical Applications in Genetics and Molecular Biology Linear Models and Empirical Bayes Methods for Assessing Differential Expression in Microarray Experiments , 2011 .

[40]  N. López-Bigas,et al.  Cooperation between dE2F1 and Yki/Sd defines a distinct transcriptional program necessary to bypass cell cycle exit. , 2011, Genes & development.

[41]  Lincoln D. Stein,et al.  Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes , 2012, Nature.

[42]  Laura M. Heiser,et al.  A central role for RAF→MEK→ERK signaling in the genesis of pancreatic ductal adenocarcinoma. , 2012, Cancer discovery.

[43]  Jean YH Yang,et al.  Bioconductor: open software development for computational biology and bioinformatics , 2004, Genome Biology.

[44]  M. Barbacid,et al.  Genetically engineered mouse models of pancreatic adenocarcinoma , 2013, Molecular oncology.

[45]  J. Fridlyand,et al.  Rare amplicons implicate frequent deregulation of cell fate specification pathways in oral squamous cell carcinoma , 2005, Oncogene.

[46]  H. Kocher,et al.  Pancreatic Cancer , 2019, Methods in Molecular Biology.

[47]  F. Gage,et al.  YAP regulates neural progenitor cell number via the TEA domain transcription factor. , 2008, Genes & development.

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

[49]  D. Bar-Sagi,et al.  RAS oncogenes: weaving a tumorigenic web , 2011, Nature Reviews Cancer.

[50]  David M. Thomas,et al.  The Hippo pathway and human cancer , 2013, Nature Reviews Cancer.

[51]  Ralph Weissleder,et al.  Both p16(Ink4a) and the p19(Arf)-p53 pathway constrain progression of pancreatic adenocarcinoma in the mouse. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[52]  Prasenjit Dey,et al.  Genetics and biology of pancreatic ductal adenocarcinoma , 2006, Genes & development.

[53]  M. Wigler,et al.  Identification and Validation of Oncogenes in Liver Cancer Using an Integrative Oncogenomic Approach , 2006, Cell.

[54]  Bin Zhao,et al.  The Hippo pathway in organ size control, tissue regeneration and stem cell self-renewal , 2011, Nature Cell Biology.

[55]  R. Rad,et al.  Selective requirement of PI3K/PDK1 signaling for Kras oncogene-driven pancreatic cell plasticity and cancer. , 2013, Cancer cell.

[56]  H. Pasolli,et al.  Yes-associated protein (YAP) transcriptional coactivator functions in balancing growth and differentiation in skin , 2011, Proceedings of the National Academy of Sciences.

[57]  Frank McCormick,et al.  Cancer therapy based on oncogene addiction , 2011, Journal of surgical oncology.