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

Priscilla Cheung; Jordi Xiol; Michael T Dill; Wei-Chien Yuan; Riccardo Panero; Jatin Roper; Fernando G Osorio; Dejan Maglic; Qi Li; Basanta Gurung; Raffaele A Calogero; Ömer H Yilmaz; Junhao Mao; Fernando D Camargo

doi:10.1016/j.stem.2020.07.003

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

Cell Stem Cell. 2020 Oct 1;27(4):590-604.e9. doi: 10.1016/j.stem.2020.07.003. Epub 2020 Jul 29.

Authors

Affiliations

¹ Stem Cell Program, Boston Children's Hospital, Boston, MA 02115, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
² Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, 10126 Torino, Italy.
³ Division of Gastroenterology, Department of Medicine, Duke University, Durham, NC 27710, USA; Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.
⁴ Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
⁵ Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA; Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
⁶ Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
⁷ Stem Cell Program, Boston Children's Hospital, Boston, MA 02115, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA. Electronic address: fernando.camargo@childrens.harvard.edu.

Abstract

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.

Keywords: Hippo signaling; Wnt signaling; colorectal cancer; intestinal stem cells; metastasis; regeneration.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / metabolism
Animals
Cell Cycle Proteins*
Cell Proliferation
Colorectal Neoplasms*
Mice
Phosphoproteins / metabolism
Transcription Factors

Substances

Adaptor Proteins, Signal Transducing
Cell Cycle Proteins
Phosphoproteins
Transcription Factors

Abstract

Publication types

MeSH terms

Substances

Grants and funding