Survivin promotes stem cell competence for skin cancer initiation

Abstract Stem cells (SC) and not progenitors (P) act as cells of origin of basal cell carcinoma (BCC). The mechanisms promoting BCC formation in SCs or restricting tumor development in Ps are currently unknown. In this study, we transcriptionally profiled SCs and Ps and found that Survivin, a pleiotropic factor that promotes cell division and inhibits apoptosis, was preferentially expressed in SCs. Using genetic gain- and loss-of-function mouse models, we showed that Survivin deletion in oncogene-expressing SCs prevents BCC formation. Survivin overexpression renders Ps competent to BCC formation by promoting cell survival and division while preventing apoptosis and differentiation. We identified Serum glucocorticoid–regulated kinase 1 (Sgk1) as a key downstream factor of Survivin and that its inhibition prevents BCC formation. This study uncovers the role and mechanisms by which Survivin regulates the competence of SCs to initiate BCC formation, promoting the survival of oncogene-expressing SCs and self-renewing division while restricting differentiation and apoptosis. Significance: This study identifies Survivin as a key regulator of the different ability of SCs and Ps to initiate skin cancer. Survivin expression in oncogene-targeted SCs is essential for their survival and self-renewal and to prevent their differentiation and apoptosis, allowing SCs and not Ps to initiate skin cancer.