Peritumoral YAP and TAZ Expression Suppresses Tumor Growth in Mice

Hyperactivation of the Hippo signaling pathway via upregulation of its two downstream effectors, the transcriptional coactivators YAP and TAZ, has been shown to promote tumorigenesis. In a mouse model of intrahepatic cholangiocarcinoma, Moya, Castaldo, Van den Mooter, Soheily, and colleagues detected large amounts of YAP and TAZ in tumor cells, as expected. However, there was also YAP accumulation in peritumoral hepatocytes and an increase in expression of classic YAP targets along with an increase in a proliferation marker in these cells. Deletion of Yap and the homologous Taz in normal hepatocytes but not tumor cells increased tumor-cell proliferation, resulting in increased tumor burden, implying that YAP and TAZ in peritumoral hepatocytes normally function to restrict tumor growth. Consistent with this notion, condtional deletion of the genes encoding the YAP and TAZ inhibitors LATS1 and LATS2 in peritumoral hepatocytes substantially diminished tumor growth, and conditional overexpression of a constitutively active form of human YAP in the normal liver cells caused tumor regression in the mice. Further investigation revealed that activation of YAP or TAZ in peritumoral hepatocytes exerted its antitumor effects by inducing nonapoptotic programmed cell death in the tumor cells. Notably, the tumor cells required YAP and TAZ for survival only when the surrounding cells possessed wild-type YAP and TAZ. The tumor-suppressive effects of peritumoral YAP and TAZ extended to a mouse model of hepatocellular carcinoma as well as a mouse model of aggressive, NRAS-mutant melanoma that had metastasized to the liver. Together, these results suggest that cell competition akin to that originally detailed in Drosophila may be at work; specifically, the dependence of tumor cells on YAP and TAZ was specified by the levels of YAP and TAZ in the surrounding normal tissue. Given the interest in developing YAP- and TAZ-targeting drugs, further work to determine whether this effect is present in humans is needed, as it implies that systemic inhibition of YAP and TAZ may actually have protumorigenic effects.

Moya IM, Castaldo SA, Van den Mooter L, Soheily S, Sansores-Garcia L, Jacobs J, et al. Peritumoral activation of the Hippo pathway effectors YAP and TAZ suppresses liver cancer in mice. Science;366:1029–34.

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