Cancer stem cells (CSCs) have been reported in various cancers, including in skin squamous-cell carcinoma (SCC)1,2,3,4. The molecular mechanisms regulating tumour initiation and stemness are still poorly characterized. Here we find that Sox2, a transcription factor expressed in various types of embryonic and adult stem cells5,6, was the most upregulated transcription factor in the CSCs of squamous skin tumours in mice. SOX2 is absent in normal epidermis but begins to be expressed in the vast majority of mouse and human pre-neoplastic skin tumours, and continues to be expressed in a heterogeneous manner in invasive mouse and human SCCs. In contrast to other SCCs, in which SOX2 is frequently genetically amplified7, the expression of SOX2 in mouse and human skin SCCs is transcriptionally regulated. Conditional deletion of Sox2 in the mouse epidermis markedly decreases skin tumour formation after chemical-induced carcinogenesis. Using green fluorescent protein (GFP) as a reporter of Sox2 transcriptional expression (SOX2–GFP knock-in mice), we showed that SOX2-expressing cells in invasive SCC are greatly enriched in tumour-propagating cells, which further increase upon serial transplantations. Lineage ablation of SOX2-expressing cells within primary benign and malignant SCCs leads to tumour regression, consistent with the critical role of SOX2-expressing cells in tumour maintenance. Conditional Sox2 deletion in pre-existing skin papilloma and SCC leads to tumour regression and decreases the ability of cancer cells to be propagated upon transplantation into immunodeficient mice, supporting the essential role of SOX2 in regulating CSC functions. Transcriptional profiling of SOX2–GFP-expressing CSCs and of tumour epithelial cells upon Sox2 deletion uncovered a gene network regulated by SOX2 in primary tumour cells in vivo. Chromatin immunoprecipitation identified several direct SOX2 target genes controlling tumour stemness, survival, proliferation, adhesion, invasion and paraneoplastic syndrome. We demonstrate that SOX2, by marking and regulating the functions of skin tumour-initiating cells and CSCs, establishes a continuum between tumour initiation and progression in primary skin tumours.
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We thank our colleagues who provided us with reagents. We also thank the animal house facility of the Université Libre de Bruxelles (ULB) (Erasme campus). C.B. is an investigator of WELBIO. S.Bo., B.B., B.D., S.Br., G.L. and D.N. are supported by a FNRS/FRIA, FNRS and TELEVIE fellowships. G.D. is supported by the Brussels Region through the BB2B program. This work was supported by the FNRS, TELEVIE, BB2B program, the IUAP program, a research grant from the Fondation Contre le Cancer, the ULB foundation, the Fonds Yvonne Boël, the Fonds Gaston Ithier, the foundation Bettencourt Schueller, and a starting grant from the European Research Council.
Extended data figures
Table presenting the 39 genes between the genes upregulated in the SOX2+ CSC signature and downregulated following SOX2 deletion. ESC = embryonic stem cells; GB = glioblastoma cell line ; Y = yes; N= no.
Table presenting: a) the 57 genes of the overlap between the genes downregulated following SOX2 deletion in skin TECs and downregulated in an inducible Sox-null mouse ES cells (SOX2-cKO). b) the 46 genes downregulated in the SOX2 regulated gene signature and bound by SOX2 in ES cells (but not downregulated in SOX2-cKO in ES cells). ESC = embryonic stem cells ; Y = yes; N= no.
Table presenting: a) the 5 common genes of the overlap between the genes downregulated in the SOX2 regulated gene signature and genes downregulated (fold>2) in a transient knock-down of SOX2 in human glioblastoma cell line (SOX2 KD). b) the 49 genes downregulated in the SOX2 regulated gene signature and bound by SOX2 in human glioblastoma cell line (but not donwregulated in SOX2KD). GB = glioblastoma cell line ; Y = yes; N= no.
Table presenting the primers and corresponding binding site used for Chip-qPCR.
Table presenting the list of the human skin SCCs samples used in this study.
Table presenting the primers used for qRT-PCR.
About this article
Cellular and Molecular Life Sciences (2019)