Inducible formation of leader cells driven by CD44 switching gives rise to collective invasion and metastases in luminal breast carcinomas

Collective invasion into adjacent tissue is a hallmark of luminal breast cancer, and similar to 20% of these cases eventually undergo metastasis. How less aggressive luminal-like breast cancer transitions to invasive cancer remains unclear. Our study revealed that CD44(hi) cancer cells are the leading subpopulation in collectively invading luminal cancer cells and efficiently promote the collective invasion of CD44(lo)/follower cells. The CD44(hi)/leader subpopulation showed a specific gene signature of various hybrid epithelial/mesenchymal genes and key functional coregulators of collective invasion, which was distinct from that of CD44(lo)/follower cells. However, the CD44(hi)/leader cells, which showed a partial epithelial-mesenchymal transition (EMT) phenotype, readily switched to the CD44(lo) phenotype along with collective migration and vice versa; this phenomenon was spontaneous and sensitive to the tumor microenvironment. The CD44(lo)-to-CD44(hi) conversion was accompanied by a shift in CD44s to CD44v but not a conversion of non-cancer stem cells to cancer stem cells (CSCs). Therefore, the CD44(hi) leader cells, as currently identified, are not a stable subpopulation in breast tumors. This plasticity and ability to generate CD44(hi) carcinoma cells with enhanced migratory and invasive behavior might be responsible for the transition from in situ to invasive behavior of luminal-type breast cancer.