Research ArticleCancer

Downstream of Mutant KRAS, the Transcription Regulator YAP Is Essential for Neoplastic Progression to Pancreatic Ductal Adenocarcinoma

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Sci. Signal.  06 May 2014:
Vol. 7, Issue 324, pp. ra42
DOI: 10.1126/scisignal.2005049

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Targeting YAP to Promote the Antitumor Response

Pancreatic ductal adenocarcinoma is frequently associated with mutations in KRAS, but targeting RAS proteins is clinically challenging. From studies with genetically engineered mouse models and correlations in human samples, Zhang et al. determined that the protein YAP mediated the transition from pancreatic metaplasia to invasive adenocarcinoma by transcriptionally activating genes induced by KRAS signaling. Deleting Yap in Kras or Kras:Trp53 mutant mouse pancreatic epithelia prevented their proliferation, decreased the expression and secretion of KRAS-regulated proteins that mediate inflammation and migration, and promoted immune cell infiltration in the tumor microenvironment in mice. Because Yap deletion did not affect normal pancreatic development or function, the findings indicate that Yap may be a viable target for KRAS-mutant PDAC.