Although it has been shown that the tumor extracellular matrix (ECM) may sustain the cancer stem cell (CSC) niche, its role in the modulation of CSC properties remains poorly characterized. To elucidate this, paired tumor and adjacent normal mucosa, derived from colon cancer patients’ surgical resections, were decellularized and recellularized with two distinct colon cancer cells, HT-29 or HCT-15. Methods: The matrix impact on cancer stem cell marker expression was evaluated by flow cytometry and qRT-PCR, while transforming growth factor-β (TGF-β) secretion and matrix metalloprotease (MMP) activity were quantified by ELISA and zymography. Results: In contrast to their paired normal counterparts, the tumor decellularized matrices enhanced HT-29 expression of the pluripotency and stemness genes NANOG (p = 0.0117), SOX2 (p = 0.0156), and OCT4 (p = 0.0312) and of the epithelial-to-mesenchymal transition (EMT)-associated transcription factor SNAI1 (p = 0.0156). Notably, no significant differences were found in the expression of SLUG or TGFB on HT-29 or of the six transcripts on HCT-15 cells. HT-29 mRNA alterations were followed by enhanced expression of the stemness-associated receptors cluster of differentiation 44 (CD44), CD133, and CD166 (p = 0.0078), the secretion of TGF-β (p = 0.0286), and MMP-2 (p = 0.0081) and MMP-9 (p = 0.0402) proteolysis. To infer the clinical relevance of these findings, we assessed cohort databases and evidenced that patients expressing higher levels of the four stemness-associated genes (NANOG/SOX2/OCT4/SNAI1) had worse overall survival. This study demonstrates that normal and tumor matrices harbor different stemness potential and suggest patient-derived decellularized matrices as an excellent three-dimensional (3D) model to unveil stemness signatures, appointing candidates for future therapeutic strategies.

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.

Genetic sequence of the Survivin GOF-IRES-mCherry mice generated

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.