Integration of focal adhesion morphogenesis and polarity by DOCK5 promotes YAP/TAZ-driven drug resistance in TNBC

Abstract

YAP and TAZ are transcriptional co-activators that are inhibited by sequestration in the cytoplasm. Cellular signalling pathways integrate soluble, mechanical (cytoskeleton, adhesion), and geometric (cell size, morphology) cues to regulate the translocation of YAP/TAZ to the nucleus. In triple-negative breast cancer (TNBC) cells, both signalling and morphogenesis are frequently rewired, leading to increased YAP/TAZ translocation, which drives proliferation, invasion, and drug resistance. However, whether this increased YAP/TAZ translocation is due to alterations in upstream signalling events or changes in cell morphology remains unclear. To gain insight into YAP/TAZ regulation in TNBC cells, we performed multiplexed quantitative genetic screens for YAP/TAZ localisation and cell shape, enabling us to determine whether changes in YAP/TAZ localisation following gene knockdown could be explained by alterations in cell morphology. These screens revealed that the focal adhesion (FA)-associated RhoGEF DOCK5 is essential for YAP/TAZ nuclear localisation in TNBC cells. DOCK5-defective cells exhibit defects in FA morphogenesis and fail to generate a stable, polarised leading edge, which we propose contributes to impaired YAP/TAZ translocation. Mechanistically, we implicate DOCK5's ability to act as a RacGEF and as a scaffold for NCK/AKT as key to its role in FA morphogenesis. Importantly, DOCK5 is essential for promoting the resistance of LM2 cells to the clinically used MEK inhibitor Binimetinib. Taken together, our findings suggest that DOCK5's role in TNBC cell shape determination drives YAP/TAZ upregulation and drug resistance.