Cytokinesis Failure Triggers Hippo Tumor Suppressor Pathway Activation

• Published in: Biocell 2014-08, Vol.158 (4), p.833-848
• Main Authors: Ganem, Neil J., Cornils, Hauke, Chiu, Shang-Yi, O’Rourke, Kevin P., Arnaud, Jonathan, Yimlamai, Dean, Théry, Manuel, Camargo, Fernando D., Pellman, David
• Format: Article
• Language: English
• Subjects: Cell Line, Tumor; Centrosome - metabolism; Cytokinesis; Epithelial Cells - metabolism; Hepatocytes - metabolism; Humans; Intercellular Signaling Peptides and Proteins - metabolism; Life Sciences; Neoplasms - metabolism; Neoplasms - pathology; Protein-Serine-Threonine Kinases - metabolism; rhoA GTP-Binding Protein - metabolism; Signal Transduction; Tetraploidy; Tumor Suppressor Protein p53 - metabolism; Tumor Suppressor Proteins - metabolism
• ISSN: 0092-8674; 0327-9545; 1097-4172; 1667-5746
• DOI: 10.1016/j.cell.2014.06.029

Genetically unstable tetraploid cells can promote tumorigenesis. Recent estimates suggest that ∼37% of human tumors have undergone a genome-doubling event during their development. This potentially oncogenic effect of tetraploidy is countered by a p53-dependent barrier to proliferation. However, the cellular defects and corresponding signaling pathways that trigger growth suppression in tetraploid cells are not known. Here, we combine RNAi screening and in vitro evolution approaches to demonstrate that cytokinesis failure activates the Hippo tumor suppressor pathway in cultured cells, as well as in naturally occurring tetraploid cells in vivo. Induction of the Hippo pathway is triggered in part by extra centrosomes, which alter small G protein signaling and activate LATS2 kinase. LATS2 in turn stabilizes p53 and inhibits the transcriptional regulators YAP and TAZ. These findings define an important tumor suppression mechanism and uncover adaptive mechanisms potentially available to nascent tumor cells that bypass this inhibitory regulation. [Display omitted] •Tetraploid cells activate the Hippo tumor suppressor pathway in vitro and in vivo•Extra centrosomes and altered G protein signaling trigger LATS2 activation•Active LATS2 stabilizes p53 and inactivates YAP/TAZ in tetraploid cells•Evolution experiments identify adaptations that bypass Hippo pathway activation Cells counter the oncogenic effects of tetraploidy by activating the Hippo tumor suppressor pathway, which is triggered in part by extra centrosomes, which alter small G protein signaling and activate LATS2 kinase. LATS2 in turn stabilizes p53 and inhibits the transcriptional regulators YAP and TAZ.