FAK-SFK Signaling Integrates ECM Rigidity Sensing and Engagement of ERBB2 to Activate YAP and Promote Invasive Growth and Metastasis in Breast Cancer

We have examined the mechanism through which fibrotic extracellular matrices promote tumor progression and metastasis in HER2+ breast cancer. We found that integrin-mediated mechano-transduction and engagement of ERBB2/ERBB3 cooperate to induce activation of YAP and invasive growth in stiff 3D Matrigel-Collagen I. Mechanistic studies revealed that joint activation of SRC Family Kinases (SFKs) by FAK and ERBB2/3 results in tyrosine phosphorylation and inactivation of LATS1/2 and MOB1. The ensuing activation of YAP enables HER2+ breast cancer cells to proliferate and invade in 3D Matrigel-Collagen I. In addition, tyrosine phosphorylation of LATS1/2 and MOB1 and activation of YAP are required for v-SRC-mediated transformation of fibroblasts. Finally, preclinical studies indicated that FAK-SRC signaling is required for primary tumor growth and lung metastasis in the MMTV-Neu mouse model of HER2+ breast cancer. Congruently, administration of dasatinib significantly increased the capacity of lapatinib to inhibit primary tumor growth and lung colonization in MMTV-Neu mice. These findings indicate that integrin-mediated mechano-transduction functions as a rheostat to regulate ERBB2 signaling to YAP and suggest that co-targeting ERBB2 and SFKs may exhibit therapeutic efficacy in HER2+ breast cancer. Significance statementStromal stiffness, which ensues from increased deposition and crosslinking of linear collagens, promotes oncogenesis and tumor progression in the breast. Moreover, tumor fibrosis is increased in the more aggressive subtypes of breast cancer, such as Triple Negative (TN) and HER2+ breast cancer. However, the mechanisms through which extracellular matrix stiffness regulates intracellular signaling are poorly understood. In this study, we show that the Focal Adhesion Kinase (FAK)-SRC Family Kinase (SFK) complex integrates the sensing of matrix rigidity by integrins and the activation of ERBB2/3 to promote activation of YAP and that YAP is required for breast cancer growth and invasion. Mechanistic studies demonstrate that SFKs can phosphorylate and inhibit LATS1 and MOB1, leading to activation of YAP. Simultaneous inhibition of ERBB2/3 with lapatinib and SFKs with dasatinib profoundly inhibits primary tumor growth and metastasis in a mouse model of HER2+ breast cancer. These findings suggest that the therapeutic efficacy of combinatorial blockade of ERBB2 and integrin-mediated mechano-transduction should be tested in biomarker-driven clinical trials.