Regenerative Reprogramming of the Intestinal Stem Cell State via Hippo Signaling Suppresses Metastatic Colorectal Cancer.

Journal Article (Journal Article)

Although the Hippo transcriptional coactivator YAP is considered oncogenic in many tissues, its roles in intestinal homeostasis and colorectal cancer (CRC) remain controversial. Here, we demonstrate that the Hippo kinases LATS1/2 and MST1/2, which inhibit YAP activity, are required for maintaining Wnt signaling and canonical stem cell function. Hippo inhibition induces a distinct epithelial cell state marked by low Wnt signaling, a wound-healing response, and transcription factor Klf6 expression. Notably, loss of LATS1/2 or overexpression of YAP is sufficient to reprogram Lgr5+ cancer stem cells to this state and thereby suppress tumor growth in organoids, patient-derived xenografts, and mouse models of primary and metastatic CRC. Finally, we demonstrate that genetic deletion of YAP and its paralog TAZ promotes the growth of these tumors. Collectively, our results establish the role of YAP as a tumor suppressor in the adult colon and implicate Hippo kinases as therapeutic vulnerabilities in colorectal malignancies.

Full Text

Duke Authors

Cited Authors

  • Cheung, P; Xiol, J; Dill, MT; Yuan, W-C; Panero, R; Roper, J; Osorio, FG; Maglic, D; Li, Q; Gurung, B; Calogero, RA; Yilmaz, ÖH; Mao, J; Camargo, FD

Published Date

  • October 1, 2020

Published In

Volume / Issue

  • 27 / 4

Start / End Page

  • 590 - 604.e9

PubMed ID

  • 32730753

Electronic International Standard Serial Number (EISSN)

  • 1875-9777

Digital Object Identifier (DOI)

  • 10.1016/j.stem.2020.07.003

Language

  • eng

Conference Location

  • United States