Inducible formation of leading cells driven by CD44 switching gives rise to collective invasion

Collective invasion into adjacent tissue is a hallmark of luminal breast cancer, with about 20% of cases that eventually undergo metastasis. It remained unclear how less aggressive luminal-like breast cancer transit to invasive cancer. Our study revealed that CD44hi cancer cells are the leading subpopulation in collective invading cancer cells, which could efficiently lead the collective invasion of CD44lo/follower cells. CD44hi/leading subpopulation showed specific gene signature of a cohort of hybrid epithelial/mesenchymal state genes and key functional co-regulators of collective invasion, which was distinct from CD44lo/follower cells. However, the CD44hi/leading cells, in partial-EMT state, were readily switching to CD44lo phenotype along with collective movements and vice versa, which is spontaneous and sensitive to tumor microenvironment. The CD44lo-to-CD44hi conversion is accompanied with a shift of CD44s-to-CD44v, but not corresponding to the conversion of non-CSC-to-CSC. Therefore, the CD44hi leader cells are not a stable subpopulation in breast tumors. This plasticity and ability to generate CD44hi carcinoma cells with enhanced invasion-initiating powers might be responsible for the transition from in situ to invasive behavior of luminal-type breast cancer.