Snail maintains the stem/progenitor state of skin epithelial cells and carcinomas through the autocrine effect of matricellular protein Mindin

Preservation of a small population of cancer stem cells (CSCs) within a heterogeneous carcinoma serves as a paradigm to understand how select cells in a tissue maintain their undifferentiated status. In both embryogenesis and cancer, Snail has been correlated with stemness, but the molecular underpinning of this phenomenon remains largely ill-defined. In models of cutaneous squamous cell carcinoma (cSCC), we discovered a non-epithelial-mesenchymal transition function for the transcription factor Snail in maintaining the stemness of epidermal keratinocytes. Snail-expressing cells secrete the matricellular protein Mindin, which functions in an autocrine fashion to activate a Src-STAT3 pathway to reinforce their stem/progenitor phenotype. This pathway is activated by the engagement of Mindin with the leukocyte-specific integrin, CD11b (ITGAM), which is also unexpectedly expressed by epidermal keratinocytes. Interestingly, disruption of this signaling module in human cSCC attenuates tumorigenesis, suggesting that targeting Mindin would be a promising therapeutic approach to hinder cancer recurrence. [Display omitted] •Non-EMT role of Snail in maintaining stemness of epithelial cells•Snail-expressing keratinocytes secrete Mindin to maintain stem/progenitor state•αMβ2 on epidermal keratinocytes acts as a ligand for Mindin•The Mindin signaling pathway is crucial for cancer stem cell repopulation of tumors Cancer stem cells are important for tumor initiation, growth, metastasis, and relapse after chemotherapy. Badarinath et al. report the discovery of a potential therapeutic target to eliminate cancer stem cells in skin tumors and potentially other tumors in the body.