Gene expression profile of diploid and tetraploid mouse primary hepatocyte

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 genome-scale 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. Furthermore, our experiments uncover adaptations that allow nascent tumor cells to bypass this inhibitory regulation.

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Ganem NJ, Cornils H, Chiu SY, O'Rourke KP, Arnaud J, Yimlamai D, Théry M, Camargo FD, Pellman D