Src activation in lipid rafts confers epithelial cells with invasive potential to escape from apical extrusion during cell competition

Abnormal/cancerous cells within healthy epithelial tissues undergo apical extrusion to protect against carcinogenesis, while they acquire invasive capacity once carcinogenesis progresses. However, the molecular mechanisms by which cancer cells escape from apical extrusion and invade surrounding tissues remain elusive. We found that during competition within epithelial cell layers, Src-transformed cells underwent basal delamination by Src activation within lipid rafts, whereas they were apically extruded when Src was outside of lipid rafts. Comparative analysis of contrasting phenotypes revealed that activation of the Src-STAT3-MMP axis through lipid rafts was required for basal delamination. CUB domain-containing protein 1 (CDCP1) was identified as an Src activating scaffold in lipid rafts, and its overexpression induced basal delamination. In renal cancer spheroids, CDCP1 promoted HGF-dependent invasion by activating the Src-STAT3-MMP axis. Overall, these results suggest that Src activation in lipid raft confers resistance to apical extrusion and invasive potential on epithelial cells to promote carcinogenesis.