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

被引：163

作者：

Cheung, Priscilla ^{[1
,2
]}

Xiol, Jordi ^{[1
,2
]}

Dill, Michael T. ^{[1
,2
,11
]}

Yuan, Wei-Chien ^{[1
,2
]}

Panero, Riccardo ^{[3
]}

Roper, Jatin ^{[4
,5
]}

Osorio, Fernando G. ^{[1
,2
]}

Maglic, Dejan ^{[1
,2
]}

Li, Qi ^{[6
,7
]}

Gurung, Basanta ^{[1
,2
]}

Calogero, Raffaele A. ^{[3
]}

Yilmaz, Omer H. ^{[8
,9
,10
]}

Mao, Junhao ^{[6
]}

Camargo, Fernando D. ^{[1
,2
]}

机构：

[1] Boston Childrens Hosp, Stem Cell Program, Boston, MA 02115 USA

[2] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA

[3] Univ Torino, Mol Biotechnol Ctr, Dept Mol Biotechnol & Hlth Sci, I-10126 Turin, Italy

[4] Duke Univ, Dept Med, Div Gastroenterol, Durham, NC 27710 USA

[5] Duke Univ, Dept Pharmacol & Canc Biol, Durham, NC 27710 USA

[6] Univ Massachusetts, Dept Mol Cell & Canc Biol, Med Sch, Worcester, MA 01605 USA

[7] Univ Massachusetts, Med Sch, Program Mol Med, Worcester, MA 01605 USA

[8] MIT, Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA

[9] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA

[10] Harvard Med Sch, Boston, MA 02114 USA

[11] Univ Hosp Heidelberg, Dept Gastroenterol & Hepatol, D-69120 Heidelberg, Germany

来源：

CELL STEM CELL | 2020年 / 27卷 / 04期

关键词：

IN-VITRO EXPANSION; WNT/BETA-CATENIN; GENE-EXPRESSION; PROTEIN YAP; MOUSE MODEL; PATHWAY; COLON; TRANSPLANTATION; HOMEOSTASIS; YAP/TAZ;

D O I：

10.1016/j.stem.2020.07.003

中图分类号：

Q813 [细胞工程];

学科分类号：

100113 [医学细胞生物学];

摘要：

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.

引用

页码：590 / +

页数：24

共 76 条

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