Role of YAP/TAZ in liver tumorigenesis and mammary gland cells dedifferentiation

YAP and TAZ are two transcriptional co-factors implicated in regulating fundamental biological processes, such as proliferation, regeneration, cell fate plasticity and tumorigenesis. Many upstream stimuli, such as the Hippo pathway and biomechanical inputs, regulate YAP/TAZ function. However, to date, our understanding of YAP/TAZ regulation is limited. Here I present our work on the role of SWI/SNF chromatin-remodeling complex, as YAP/TAZ nuclear inhibitor. By different in vitro assays, we found that SWI/SNF inactivation remarkably promotes YAP/TAZ-driven cell proliferation, and that the SWI/SNF component more relevant for this control is the tumor suppressor Arid1a, acting as YAP/TAZ inhibitor. In the first part of this thesis, we validate SWI/SNF tumor suppressive functions in vivo, focusing on liver tumorigenesis induced either by Hippo pathway inactivation or by chronic damage induced by the hepato-toxic compound DDC. In both of these set ups, we found that inactivation of Arid1a robustly activates YAP/TAZ, giving rise to liver tumorigenesis. Our findings prompted us to speculate that SWI/SNF can exert its tumor-suppressor function by inhibiting YAP/TAZ. Work recently published from our laboratory showed that ectopic expression of YAP/TAZ may confer stemness characteristics to normal mammary luminal differentiated cells (LD), converting them into Mammary Stem Cells-like cells (yMaSCs). In the second part of this thesis we expanded on this topic, and characterized early colonies arising from LD cells after YAP transfection. We found that a significant fraction of the genes upregulated upon LD to yMaSC transformation corresponds to genes specially expressed in the fetal mammary gland. This suggests that early colonies represent a fetal-like cellular state that is distinct from adult progenitors. In sum, this work focuses on the nuclear regulation of YAP/TAZ, offering shed new light on the enigmatic functions of an important tumor suppressor (ARID1a), and also expand on the biological consequences of YAP-induced stemness and cell plasticity.