Inflammatory Monocytes Constrain YAP-Induced Cell Proliferation [bulk RNA-seq]

YAP and its paralog, TAZ are transcriptional co-activators 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 de-differentiate 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, YAPHigh colorectal cancer (CRC) patients had a 67% 5-year survival rate, while TAZHigh CRC patients did not survive to 5 years. Similar trends were seen in hepatocellular carcinoma patients. These findings underscore the importance of understanding the intrinsic differences in YAP and TAZ biology as independent drivers of disease.