Peritumoral activation of the Hippo pathway effectors YAP and TAZ suppresses liver cancer in mice

Liver tumors activate a regeneration-like genetic program in surrounding liver tissue akin to the regeneration program activated by toxic liver injury. Using genetically engineered mouse models we show that this program is regulated by the Hippo pathway. Our results identify a novel mechanism of non-autonomous tumor suppression where activation of a regeneration-like program in normal cells around liver tumors caused tumor cell death and tumor regression. Strikingly, deleting YAP specifically in peritumoral hepatocytes resulted in hepatocyte death and enhanced tumor growth, while hyperactivating YAP in peritumoral hepatocytes caused the elimination of tumor cells and tumor regression. RNA-seq from purified hepatocytes (wild type and peritumoral) and from livers exposed to toxic injury (24 and 48h after TAA).