Prior to Undergoing Epithelial to Mesenchymal Transition, Premalignant Cells Transiently Increase Tensile Forces at Cell-Cell and Cell-Matrix Adhesions

Abstract

The weakening of Adherens Junctions (AJs) and Focal Adhesions (FAs) adhesiveness has been proposed to enable the initiation and progression of several types of cancer. Here we report that, prior to disassembling AJs and acquiring malignant traits, premalignant mammary epithelial cells overactivating the Src proto-oncogene transiently enhance tensile forces at both AJs and FAs, thereby gaining a proliferative advantage. We show that AJs and FAs are transiently under higher tensile forces in premalignant Src-activated cells. Cells unable to increase tensile forces at FAs by knocking down PXN or inhibiting FAK activity fail to transiently build up tensile force at AJs and to grow. Conversely, preventing AJ strengthening using EGTA or small interference RNA against P-cadherin suppresses the transient increase in tensile forces at FAs, EGFR-ERK and MRTF-A-SRF activation and cell proliferation. Moreover, knocking down E-cadherin, the sole classical cadherin in Drosophila, inhibits Src-induce tissue overgrowth in vivo. Thus, prior to the loss of cell-cell and cell-matrix adhesiveness, strengthening of AJs and FAs may be an essential early step for mammary cells to gain a proliferative advantage and establish the mechanical and signaling conditions necessary for subsequent malignant transformation. Statement of SignificanceAlthough the weakening of cell-cell and cell-matrix adhesiveness is commonly associated with cancer initiation and progression, our findings reveal that an initial increase in adhesiveness enables proliferation and malignant progression.