title: SOX2 controls tumour initiation and cancer stem-cell functions in squamous-cell carcinoma.
abstract: Cancer stem cells (CSCs) have been reported in various cancers, including in skin squamous-cell carcinoma (SCC). 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 cells, 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 amplified, 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.
authors.affiliation: Université Libre de Bruxelles, IRIBHM, Brussels B-1070, Belgium.
authors.forename: Soufiane
authors.initials: S
authors.lastname: Boumahdi
authors.affiliation: 1] Université Libre de Bruxelles, IRIBHM, Brussels B-1070, Belgium [2].
authors.forename: Gregory
authors.initials: G
authors.lastname: Driessens
authors.affiliation: 1] Université Libre de Bruxelles, IRIBHM, Brussels B-1070, Belgium [2].
authors.forename: Gaelle
authors.initials: G
authors.lastname: Lapouge
authors.affiliation: 1] Department of Pathology, Erasme Hospital, Université Libre de Bruxelles, Brussels B-1070, Belgium [2] DIAPATH-Center for Microscopy and Molecular Imaging (CMMI), Gosselies B-6041, Belgium.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Rorive
authors.affiliation: Université Libre de Bruxelles, IRIBHM, Brussels B-1070, Belgium.
authors.forename: Dany
authors.initials: D
authors.lastname: Nassar
authors.affiliation: Department of Pathology, Erasme Hospital, Université Libre de Bruxelles, Brussels B-1070, Belgium.
authors.forename: Marie
authors.initials: M
authors.lastname: Le Mercier
authors.affiliation: Laboratory of Cancer Epigenetics, Université Libre de Bruxelles, Brussels B-1070, Belgium.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Delatte
authors.affiliation: Université Libre de Bruxelles, IRIBHM, Brussels B-1070, Belgium.
authors.forename: Amélie
authors.initials: A
authors.lastname: Caauwe
authors.affiliation: Université Libre de Bruxelles, IRIBHM, Brussels B-1070, Belgium.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Lenglez
authors.affiliation: Université Libre de Bruxelles, IRIBHM, Brussels B-1070, Belgium.
authors.forename: Erwin
authors.initials: E
authors.lastname: Nkusi
authors.affiliation: Machine Learning Group, Computer Science Department, Faculté des Sciences, Université Libre de Bruxelles, Brussels B-1050, Belgium.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Brohée
authors.affiliation: 1] Department of Pathology, Erasme Hospital, Université Libre de Bruxelles, Brussels B-1070, Belgium [2] DIAPATH-Center for Microscopy and Molecular Imaging (CMMI), Gosselies B-6041, Belgium.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Salmon
authors.affiliation: Université Libre de Bruxelles, IRIBHM, Brussels B-1070, Belgium.
authors.forename: Christine
authors.initials: C
authors.lastname: Dubois
authors.affiliation: Department of Dermatology, Erasme Hospital, Université Libre de Bruxelles, Brussels B-1070, Belgium.
authors.forename: Veronique
authors.initials: V
authors.lastname: del  Marmol
authors.affiliation: Laboratory of Cancer Epigenetics, Université Libre de Bruxelles, Brussels B-1070, Belgium.
authors.forename: Francois
authors.initials: F
authors.lastname: Fuks
authors.affiliation: Université Libre de Bruxelles, IRIBHM, Brussels B-1070, Belgium.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Beck
authors.affiliation: 1] Université Libre de Bruxelles, IRIBHM, Brussels B-1070, Belgium [2] WELBIO, Université Libre de Bruxelles, Brussels B-1070, Belgium.
authors.forename: Cédric
authors.initials: C
authors.lastname: Blanpain
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000473:pathology; D002448:Cell Adhesion / Q000235:genetics; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D017353:Gene Deletion; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D053263:Gene Regulatory Networks / Q000235:genetics; D051379:Mice; D008815:Mice, Inbred Strains; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism*; D012878:Skin Neoplasms / Q000235:genetics / Q000473:pathology
chemical_list: D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse