Faria, L.; Goncalves, C. M.; Fidalgo, I.; Lopes, C. S.; Rodrigues, V.; Azevedo, M. M.; Paula Sampaio, P.; Tavares, S.; Mahajan, V.; Taubenberger, A.; Janody, F.

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 demonstrate that prior to acquiring malignant features, a transient mechanical crosstalk between AJs and FAs provides a proliferative advantage to mammary epithelial cells overactivating the Src kinase proto-oncogene. We show that AJs and FAs are transiently under high tension during the early phase of cellular transformation. Preventing the strengthening of tensile forces at FAs by knocking down PXN or inhibiting FAK activity, suppresses the cell abilities to build up tension at AJs and to grow. Conversely, disrupting the trans junctional homophilic interactions between cadherin extracellular domains with EGTA or preventing AJ strengthening by knocking down P-cadherin, impedes the transient increase in tensile forces at FAs, the activation of EGFR-ERK and MRTF-A-SRF signalling and cell proliferation. Moreover, knocking down E-cadherin, the sole classical cadherin in Drosophila, inhibits the growth of Src-overexpressing tissues in vivo. Thus, prior to the loss of cell-cell and cell-matrix adhesiveness, a transient mechanical crosstalk between AJs and FAs could drive tumour growth.