Abstract SY28-01: The paradox of YAP/TAZ in cancer biology

Abstract YAP and TAZ, transcriptional co-activators and the downstream effectors of the Hippo pathway, are often hyperactivated in diverse cancers where they promote tumor growth. Inhibiting the activity of YAP/TAZ is thus an attractive strategy for the treatment of cancer. However, our findings challenge the idea that YAP/TAZ are simply tumor-promoting. Studying mouse models of liver cancer, we found that YAP/TAZ activity in peritumoral hepatocytes exerts a tumor-suppressive function. While deleting Yap/Taz in tumor cells led to tumor regression, deleting Yap/Taz in peritumoral hepatocytes unexpectedly accelerated tumor growth. Even more strikingly, tumor cells no longer required YAP/TAZ when surrounded by Yap/Taz mutant hepatocytes. These results cannot be explained by a simple mechanism whereby YAP/TAZ directly (cell autonomously) promote the proliferation and survival of tumor cells. Rather, they imply that YAP/TAZ act through a non-cell autonomous mechanism of cell competition, whereby cells with higher YAP/TAZ activity outcompete cells with lower levels. Consequently, experimental hyperactivation of YAP in peritumoral hepatocytes triggered tumor regression. We thus propose that YAP/TAZ activity dictates cellular “fitness”: YAP/TAZ are tumor promoting when higher in tumor cells, but tumor suppressing when higher in tumor-surrounding cells. These findings shift our understanding of YAP/TAZ in cancer: rather than being purely oncogenic, their activity in normal cells can lead to the suppression of tumor growth. These effects raise critical questions for YAP/TAZ-targeted therapies, suggesting that inhibiting YAP/TAZ indiscriminately may, in some contexts, accelerate tumor progression rather than suppress it. Citation Format: Georg Halder. The paradox of YAP/TAZ in cancer biology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr SY28-01.