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 carci-nogenesis, although 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. In this study, we demonstrate a molecular mechanism for cell fate switching during epithelial cell competition. We found that during competition within epithelial cell layers, Src transformation promotes maturation of focal adhesions and degradation of extracellular matrix. Src-transformed cells underwent basal delamination by Src activation within sphingolipid/cholesterol-enriched membrane microdomains/ lipid rafts, whereas they were apically extruded when Src was outside of lipid rafts. A 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-acti-vating scaffold and as a Met regulator in lipid rafts, and its overexpression induced basal delamination. In renal cancer models, CDCP1 promoted epithelial-mesenchymal transition-mediated invasive behavior by activating the Src-STAT3-MMP axis through Met activation. Overall, these results suggest that spatial acti-vation of Src signaling in lipid rafts confers resistance to apical extrusion and invasive potential on epithelial cells to promote carcinogenesis.

Automated summary

This study reveals a molecular mechanism for cell fate switching during epithelial cell competition. Src transformation promotes focal adhesion maturation and extracellular matrix degradation. Src-transformed cells undergo basal delamination within lipid rafts, while they are apically extruded when Src is outside of lipid rafts. This process is mediated by the activation of the Src-STAT3-MMP axis through lipid rafts, which requires the presence of CUB-domain-containing protein 1 (CDCP1). These findings contribute to our understanding of the mechanisms underlying cancer cell invasion.