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

Abstract

Intratumoral heterogeneity poses a major challenge in designing effective anti-cancer strategies. Accumulating evidence suggests that this heterogeneity arises from cancer stem cells (CSCs) that also drives tumor aggressiveness and drug resistance. The stemness of CSCs are preserved by an ill-defined combination of intrinsic and external factors and is particularly intriguing since they exist within a sea of similar cells at various degrees of differentiation. In models of cutaneous squamous cell carcinoma (cSCC), we discovered a non-EMT function for the transcription factor Snail in maintaining stemness of keratinocytes. This is accomplished by the secretion of the matricellular protein Mindin from Snail expressing cells, which creates a protective niche that impedes differentiation. In an autocrine fashion, extracellular Mindin activates a Src -STAT3 pathway to reinforce the stem/progenitor phenotype and disruption of this signalling module in human cSCC attenuates tumorigenesis. The expression of Mindin in multiple carcinomas, and its critical role in cancer progression suggests that it would be a promising target for therapeutic intervention.