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.

Sox2 is dispensable for primary melanoma and metastasis formation

“…in cells associated with tumor initiation and propagation 11,12 . Consistent with these data, Sox2 ablation in a SCC mouse model led to decreased tumor formation 12 . More recently, Sox2 was revealed by overexpression experiments in genetically engineered mouse models to be a driver of lung SCC 13 .…”

Pioneer transcription factors in cell reprogramming

“…Sox2 is not expressed in the normal epidermis but is up-regulated in mouse and human cancer stem cells in skin squamous cell carcinomas (Boumahdi et al 2014). There, Sox2 is involved in the initial stage of tumor formation and its maintenance.…”

“…Inducing zygotic genome activation Liang et al 2008 Increasing DNA accessibility in native chromatin Harrison et al 2011;Foo et al 2014;Xu et al 2014 Class V Pou (e.g., Oct3/4, Pou5f3) Zygotic genome activation (zebrafish/mouse) Inducing zygotic genome activation Foygel et al 2008;Lee et al 2013 Binding to target sites before zygotic genome activation Leichsenring et al 2013 Reprogramming from fibroblast to iPSCs (mouse/human) Inducing reprogramming Takahashi and Yamanaka 2006 Binding to chromatin that is not DNase-sensitive and not premarked by common histone modifications in vivo Soufi et al 2012 Group B1 Sox (e.g., Sox2) Zygotic genome activation (zebrafish/mouse) Inducing zygotic genome activation Pan and Schultz 2011;Lee et al 2013 Reprogramming from fibroblast to iPSCs (mouse/human) Inducing reprogramming Takahashi and Yamanaka 2006 Binding to chromatin that is nonhypersensitive and not premarked by common histone modifications in vivo Soufi et al 2012 Cancer progression (mouse/human) Inducing tumor formation Bass et al 2009;Boumahdi et al 2014 Klf4…”

Cancer metabolism in space and time: Beyond the Warburg effect

“…Meval onate pro duc tion was shown to be crit i cal for the ger anyl ger any la tion and proper mem brane lo cal iza tion of RhoA (Ras ho molog gene fam ily, mem ber A), a reg u la tor of self re newal and pluripo tency of stem cells [242]. In skin squa mous cell pa pil loma and car ci noma, SOX2 was iden ti fied as a key tran scrip tion fac tor re ex pressed in CSCs and con trol ling stem ness [243]. In ter est ingly, SOX2 di rectly up reg u lates the tran scrip tion of sev eral genes re lated to glu t a mine and lipid me tab o lism, but their rel e vance for the stem like prop er ties of tu mor cells re mains un known [243].…”