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

The mesenchymal-epithelial transition (MET) whether full or partial, has been implicated in secondary tumor growth during metastasis. Here, we explore whether MET enhances tumor outgrowth by boosting proliferation, using MET-inducible mesenchymal cancer cell lines. Surprisingly, we found that crowding inhibition of proliferation persists both before and after MET, however, escaping crowding conferred a proliferative advantage to mesenchymal cells. In three-dimensional culture, MET caused a reduction in proliferation, accompanied by changes in proliferative signaling of focal adhesions and actomyosin. Furthermore, co-culture experiments with peripheral blood mononuclear cells revealed that MET-induced spheroids demonstrate an increased evasion to immune cell attack. This effect is likely mediated by both a confined morphology and alterations in the expression of key immunomodulatory molecules. Together, these findings suggest that MET may contribute to secondary tumor outgrowth, not by boosting proliferation, but by enhancing survival in immune-challenging environments.