Mesenchymal-epithelial transition reduces proliferation but increases immune evasion in tumor spheroids

Abstract

Mesenchymal-epithelial transition (MET) has been associated with secondary tumor outgrowth during metastasis but the underlying mechanism remains elusive. Using MET-inducible mesenchymal breast cancer cells, we investigated whether MET benefits tumor outgrowth by enhancing proliferation. We found that crowding inhibition of proliferation is present before and after MET, but mesenchymal cells gain a proliferative advantage through more effective escape from crowded cell islands. In 3D culture, proliferation is reduced upon MET with differential effects of focal-adhesion-signalling and actomyosin activity. In particular, inhibition of Src-signalling leads to increased growth after MET. Finally, in co-culture experiments, MET-induced tumor spheroids evade immune cell attack to a larger extent, likely due to more confined epithelial spheroid shape and changes in immunomodulatory molecules. Our data suggest that, contrary to previous assumptions in the field, MET might promote secondary tumor outgrowth not through a proliferation boost but through increased survival rate in the presence of immune cells.