Integrin α3β1 in hair bulge stem cells modulates CCN2 expression and promotes skin tumorigenesis

Epidermal-specific deletion of integrin alpha 3 beta 1 almost completely prevents the formation of papillomas during 7,12-Dimethylbenz [a]anthracene/12-O-tetradecanoylphorbol-13-acetate (DMBA/TPA) two-stage skin carcinogenesis. This dramatic decrease in tumorigenesis was thought to be due to an egress and premature differentiation of alpha 3 beta 1-depleted hair bulge (HB) stem cells (SCs), previously considered to be the cancer cells-of-origin in the DMBA/ TPA model. Using a reporter mouse line with inducible deletion of alpha 3 beta 1 in HBs, we show that HB SCs remain confined to their niche regardless of the presence of alpha 3 beta 1 and are largely absent from skin tumors. However, tumor formation was significantly decreased in mice deficient for alpha 3 beta 1 in HB SCs. RNA sequencing of HB SCs isolated from short-term DMBA/TPA-treated skin showed alpha 3 beta 1-dependent expression of the matricellular protein connective tissue growth factor (CCN2), which was confirmed in vitro, where CCN2 promoted colony formation and 3D growth of transformed keratinocytes. Together, these findings show that HBs contribute to skin tumorigenesis in an alpha 3 beta 1-dependent manner and suggest a role of HB SCs in creating a permissive environment for tumor growth through the modulation of CCN2 secretion.