Issues

Garcia-Rendueles, Ricarte-Filho, and colleagues found that chr22q LOH is a common event in poorly differentiated thyroid cancer (PDTC) and is preferentially associated with RAS mutations. In mice, neither thyroid-specific activation of Hras nor Nf2 deletion was sufficient for transformation, but their combined disruption led to highly penetrant PDTC characterized by increased MAPK signaling. Inactivation of the Hippo pathway in NF2-deficient cells increased YAP-mediated transcription of wild-type and mutant RAS isoforms, whereas disruption of YAP–TEAD binding blocked RAS transcription and inhibited cancer cell growth. Additionally, NF2 loss sensitized RAS-mutant thyroid cancer cells to MEK inhibitors. These results identify YAP as a critical effector of RAS-induced tumorigenesis and suggest that inhibition of YAP or MEK may be effective in RAS-driven thyroid cancer. For details, please see the article by Garcia-Rendueles, Ricarte-Filho, and colleagues on page 1178.