Inflammatory monocytes constrain YAP-induced cell proliferation

<i>YAP</i> and its paralog, <i>TAZ</i>, are transcriptional coactivators of the Hippo pathway that regulate cell growth. Their structural distinctiveness suggests important independent functional differences. To investigate this further, we generated YAP- and TAZ-predominant clones in the liver and followed their long-term behavior. YAP clones rapidly dedifferentiate cells into a stem cell-like state with inflammatory immune cell recruitment followed by their clearance. In contrast, TAZ clones promote an anti-inflammatory immune environment, resulting in their long-term maintenance, massive organ growth, and increased mortality. YAP clones recruit inflammatory blood-derived monocytes, which, if inhibited, permits YAP clonal growth. Consistent with these results, patients with <i>YAP</i>^High colorectal cancer (CRC) had a 67% 5-year survival rate, whereas patients with <i>TAZ</i>^High CRC did not survive to 5 years. Similar trends were seen in patients with hepatocellular carcinoma. These findings underscore the importance of understanding the intrinsic differences in YAP and TAZ biology as independent drivers of disease.