Inflammatory monocytes constrain YAP-induced cell proliferation.

YAP and its paralog, TAZ, 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 YAPHigh colorectal cancer (CRC) had a 67% 5-year survival rate, whereas patients with TAZHigh 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.