Transcriptomics

Dataset Information

298

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 in the setting of KRAS suppression. In this model, the transcriptional co-activator 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 Three biological replicates of primary lung adenocarcinoma cells derived from the Kras Lox-STOP-Lox-G12D;p53flox/flox (KP) mouse lung cancer model into which a doxycycline-inducible shRNA targeting Kras expressed from the 3’UTR of GFP was introduced (KP-KrasA cells) were analyzed at timepoints (days) D0, D4, and D21.

ORGANISM(S): Mus musculus  

SUBMITTER: William C Hahn   David E Root  Arjun Bhutkar  Thomas M Roberts  Diane D Shao  Yaara Zwang  Xiaoxing Wang  Elsa B Krall  Sabina Sood  Tyler Jacks  Joseph Rosenbluh  A Bhutkar  Anna C Schinzel  Jong W Kim  Federica Piccioni  Wen Xue 

PROVIDER: E-GEOD-56175 | ArrayExpress | 2014-07-27

SECONDARY ACCESSION(S): SRP040553GSE56175PRJNA242635

REPOSITORIES: GEO, ArrayExpress, ENA

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Publications


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 suppress  ...[more]

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