Abstract SY29-03: Regulation and function of the Hippo-YAP pathway in organ size, tumorigenesis, and metastasis

Abstract

Abstract Regulation and function of the Hippo-YAP pathway in organ size, tumorigenesis and metastasis Kun-Liang Guan, Department of Pharmacology and Moores Cancer Center, University of California at San Diego, USA The Yes-associated protein (YAP) is a transcription co-activator that plays a critical role in organ size control by promoting cell proliferation and inhibiting apoptosis. YAP is a human oncogene amplified or overexpressed in some human cancers. YAP represents the major downstream of the Hippo tumor suppressor pathway. The Lats tumor suppressor kinase in the Hippo pathway phosphorylates and inactivates YAP. Recent studies have demonstrated regulation of the Hippo pathway by cell-cell contact, cell adhesion, and mechanical stress. Cell attachment to extracellular matrix (ECM) is crucial to cell physiology such as cell polarity, cell motility, and cell proliferation. In normal cells, loss of attachment to ECM induces a specific type of apoptosis, termed anoikis. In metastatic cancer cells, resistance to anoikis allows their survival in circulation and dispersion to distant anatomic sites leading to tumor metastasis. We have observed that cell detachment activates the Hippo pathway kinases Lats1/2 and leads to YAP phosphorylation and inhibition. The detachment-induced YAP inactivation is required for anoikis. Furthermore, actin and microtubule organization mediates Lats1/2 activation in response to cell detachment. Moreover, Lats2 downregulation is tightly associated with metastatic prostate cancer, indicating a role of the Hippo pathway in tumor metastasis. Our findings provide an important connection from cell attachment and cytoskeleton organization to cell proliferation, anoikis, and cancer metastasis through the Hippo pathway. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY29-03. doi:1538-7445.AM2012-SY29-03