Patel, K. R.; Shu, R. R.; Wang, R.; Tekale, K.; Hamersky, M.; Perez, A. B.; Solano, D.; Syed, N.; Stewart, C. E.; Lee, J.; Hanlon, A. M.; Blalock, T. W.; Li, C.; Seldin, L.

Epithelia maintain their barrier function by exploiting the proliferative and plastic properties of stem cells to promote continual tissue regeneration. Consequently, however, these features make epithelia prone to tumorigenesis. Skin is the largest epithelial barrier and the source of cutaneous cancers, the deadliest of which are cutaneous squamous cell carcinomas (cSCCs). Despite the pervasiveness of these cancers, however, the molecular mechanisms employed by stem cells and their microenvironment to promote skin tumor development remain poorly defined. Our previous work revealed that genotoxic damage to normal skin activates inflammasome signaling crosstalk between epidermal epithelia and fibroblasts to promote epithelial stem cell hyperproliferation and fate misspecification. We hypothesized that these phenomena would also be featured during skin cancer development. Using mouse and human skin disease specimens, we determined that in vivo stem cell misspecification is a generalizable feature across diverse pathophysiological skin conditions, including cutaneous cancers, but is not present in normal high proliferative contexts. Strikingly, in vivo inflammasome activation was observed in both the epithelial and dermal compartments of cSCC tumors but was not evident in other skin pathologies. Probing further into the mechanism, we revealed that inflammasome pathway activation in cSCC is epithelial autonomous but non-cell autonomous. Furthermore, fibroblasts juxtaposed to the cSCC epithelial tumor interface exhibited population expansion as well as IL-1 signaling activation, which was absent in overlying epithelia. Based on these findings, we propose a model whereby epithelial-to-fibroblast inflammasome crosstalk initiates a fibroblast feed-forward IL-1 signaling loop that augments the tumor-promoting cSCC milieu.