Genome-wide CRISPR screen identifies mutation-specific pathways converging on TAZ/TEAD activation in mutant p53-driven breast cancer

Most clinical mutations of TP53 are missense mutations. We previously showed that TP53 -missense mutations common in triple-negative breast cancer (TNBC) patients produce neomorphic phenotypes compared to TP53 -null cells, with the TAZ/TEAD pathway strongly associated with cell invasion in aggressive p53 mutants. But TP53 mutations alone are insufficient for full oncogenesis. We performed a genome-wide CRISPR screen to identify "co-drivers" of the weakly aggressive p53 mutation, Y234C. The loss of FGD6 (cytoskeletal regulator) and GCNT1 (glycosylation enzyme) increased invasiveness, and TAZ/TEAD activation, and the invasive phenotype was abolished by inhibition of the TAZ/TEAD signaling by either an shRNA-based TAZ-knockdown or a TEAD-antagonist. This TAZ/TEAD dependency was also observed for >85% of the top ~200 other invasion-promoting hits with highly diverse gene functions. Profiling of oncogenic pathways further identified shared and unique signaling, providing mechanistic insight into how individual co-driver mutations coordinately induce cell invasion. Taken together, these results demonstrate that FGD6 and GCNT1 mutations can co-drive cancer progression with the p53-Y234C mutation through the TAZ/TEAD signaling pathway. These diverse, seemingly unrelated mutations converge on and activate a core oncogenic process through distinct mechanisms, potentially explaining the highly heterogeneous mutation profiles observed among TNBC patients and offering a rationale for novel personalized targeted therapies.