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.

Mindin differentially regulates fibroblast subpopulations via distinct members of the Src family kinases during fibrogenesis

“…We recently observed that the matricellular protein Mindin (Spondin-2) is secreted from Snail Tg keratinocytes 18,21 and is required for the expression of inflammatory cytokines in dermal fibroblasts and fibrosis in the transgenic mouse 18 . To test if Mindin is also required for the relocalisation of Sca1+ fibroblast towards the epidermal-dermal junction in the Snail Tg skin we stained Sca1+ fibroblasts (Figure 2A) and quantified (Figure 2B, S2A) their localization in P9 WT, Snail Tg, and Snail Tg/Min KO (Mindin knockout) skin.…”

“…Our data reveals Mindin as a novel modulator of heterogeneous dermal fibroblasts that drive cutaneous fibrogenesis (Figure 5E). We have shown that Mindin is secreted by Snail Tg keratinocytes 21 and elicits unique functional responses in resident subpopulations of fibroblasts in the skin. Mindin mediates migration of Sca1+ fibroblasts via Fyn kinase and increases inflammatory cytokine production in these cells.…”

“…It is also interesting to note that scleroderma patients also have higher incidence of developing cancers 19 , suggesting that insights into this fibrotic disease would likewise shed light on the factors driving tumorigenesis. In line with this, the Snail Tg mice have also been shown to prime the skin towards the development of cutaneous squamous cell carcinoma 20,21 . The mesenchymal compartment of a fibrotic tissue has remarkable similarities to the stroma surrounding solid tumours 22,23 .…”

“…All lentiviral production and transductions were done in BSL2 in accordance with IBSC guidelines. The method for lentiviral particle generation and the shRNA-pZip-mEf1a plasmids for c-Src, Fyn and Yes shRNA (procured from transomics), have been described earlier 21 . The titre of virus that yielded greater than 50% GFP+ cells was used to transduce sorted Sca1+ or CD26+ fibroblasts after first passage, at 70-80% confluency.…”