UNRAVELING TAZ REGULATION IN BREAST CANCER BY CRISPR SCREENING

YAP and TAZ are transcriptional coactivators belonging to the Hippo signaling pathway. Their activity is regulated by a complex network of upstream signals. As consequence, they orchestrate a wide spectrum of downstream cellular responses. In physiological conditions, a precisely balanced equilibrium governs activation and inhibition of YAP/TAZ. Disruption of this equilibrium unleashes YAP/TAZ oncogenic potential, promoting the development and progression of several human malignancies. In particular, TAZ overexpression has been associated with increasing aggressiveness of breast tumors, endowing mammary gland cells with oncogenic features, as stemness properties, migration, invasion and chemoresistance. Yet, YAP/TAZ mutations or genetic alterations of their known upstream regulators are relatively rare, raising the question of how YAP/TAZ are upregulated in cancer cells. To gain insights into novel TAZ regulators within the context of breast cancer, we conducted a series of loss-of-function CRISPR/Cas9 pooled genetic screens in vitro and in vivo on a selected subset of genes, previously identified in our laboratory as modulators of TAZ transcriptional activity. With this study we aimed to identify genes crucial for breast cancer cells growth, start to investigate their mechanism of action and explore their potential functional relationship with YAP/TAZ dysregulation in cancer. Among the identified hits, we focused our attention on FERMT2 and performed an initial characterization of its pro-tumorigenic role as TAZ activator.