title: KRAS and YAP1 converge to regulate EMT and tumor survival.
abstract: Cancer cells that express oncogenic alleles of RAS typically require sustained expression of the mutant allele for survival, but the molecular basis of this oncogene dependency remains incompletely understood. To identify genes that can functionally substitute for oncogenic RAS, we systematically expressed 15,294 open reading frames in a human KRAS-dependent colon cancer cell line engineered to express an inducible KRAS-specific shRNA. We found 147 genes that promoted survival upon KRAS suppression. In particular, the transcriptional coactivator YAP1 rescued cell viability in KRAS-dependent cells upon suppression of KRAS and was required for KRAS-induced cell transformation. Acquired resistance to Kras suppression in a Kras-driven murine lung cancer model also involved increased YAP1 signaling. KRAS and YAP1 converge on the transcription factor FOS and activate a transcriptional program involved in regulating the epithelial-mesenchymal transition (EMT). Together, these findings implicate transcriptional regulation of EMT by YAP1 as a significant component of oncogenic RAS signaling.
authors: Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors: Diane D
authors: DD
authors: Shao
authors: Koch Institute for Integrative Cancer Research, Cambridge, MA 02142, USA.
authors: Wen
authors: W
authors: Xue
authors: Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors: Elsa B
authors: EB
authors: Krall
authors: Koch Institute for Integrative Cancer Research, Cambridge, MA 02142, USA.
authors: Arjun
authors: A
authors: Bhutkar
authors: Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors: Federica
authors: F
authors: Piccioni
authors: Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors: Xiaoxing
authors: X
authors: Wang
authors: Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors: Anna C
authors: AC
authors: Schinzel
authors: Koch Institute for Integrative Cancer Research, Cambridge, MA 02142, USA.
authors: Sabina
authors: S
authors: Sood
authors: Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors: Joseph
authors: J
authors: Rosenbluh
authors: Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors: Jong W
authors: JW
authors: Kim
authors: Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors: Yaara
authors: Y
authors: Zwang
authors: Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02115, USA.
authors: Thomas M
authors: TM
authors: Roberts
authors: Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors: David E
authors: DE
authors: Root
authors: Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Koch Institute for Integrative Cancer Research, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Electronic address: tjacks@mit.edu.
authors: Tyler
authors: T
authors: Jacks
authors: Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address: william_hahn@dfci.harvard.edu.
authors: William C
authors: WC
authors: Hahn
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D018797:Cell Cycle Proteins; D002470:Cell Survival; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D016503:Drug Delivery Systems; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition; D045325:HCT116 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D010750:Phosphoproteins / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors; D015533:Transcriptional Activation; D000091102:YAP-Signaling Proteins; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C117307:KRAS protein, human; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; C486223:Yap1 protein, mouse; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins