美国波士顿儿童医院Fernando D. Camargo研究组取得最新进展。他们发现通过Hippo信号的肠干细胞状态的再生性重编程抑制转移性结直肠癌（CRC）。这一成果由这一研究成果发表在2020年7月29日出版的《细胞-干细胞》杂志上。

他们证明抑制YAP活性的Hippo激酶LATS1 / 2和MST1 / 2是维持Wnt信号传导和规范的干细胞功能所必需的。Hippo抑制诱导以低Wnt信号作为标志，Wnt信号是伤口愈合反应和转录因子Klf6表达为特征的独特上皮细胞状态。

值得注意的是，LATS1 / 2的缺失或YAP的过度表达足以将Lgr5 +癌症干细胞重编程至此状态，从而抑制类器官、患者来源的异种移植以及原发性和转移性CRC小鼠模型中的肿瘤生长。最后，他们证明了YAP及其旁系同源TAZ的基因缺失促进了这些肿瘤的生长。

总的来说，他们的结果确立了YAP在成年结肠中作为肿瘤抑制因子的作用，并暗示了Hippo激酶作为大肠恶性肿瘤的治疗脆弱性。

据悉，尽管Hippo转录共激活因子YAP在许多组织中被认为是致癌的，但其在肠道稳态和CRC中的作用仍存在争议。

附：英文原文

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

Author: 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, mer H. Yilmaz, Junhao Mao, Fernando D. Camargo

Issue&Volume: 2020-07-29

Abstract: Although the Hippo transcriptional coactivator YAP is considered oncogenic in manytissues, 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 YAPactivity, 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 reprogramLgr5+ 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 growthof these tumors. Collectively, our results establish the role of YAP as a tumor suppressorin the adult colon and implicate Hippo kinases as therapeutic vulnerabilities in colorectalmalignancies.

DOI: 10.1016/j.stem.2020.07.003

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(20)30341-6