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Gene expression profile of cancer stem cells (CSCs) isolated from wild type (WT) and Sfrp1-/- mice skin squamous cell carcinoma (SCC)

ABSTRACT: Sfrp1 is a Wnt inhibitor that is down regulated in various human cancers such as acute myeloid leukaemia, hepatocellular carcinoma, pancreatic, ovarian and breast cancer etc. Our study has shown that the loss of Sfrp1 in mouse skin leads to early tumor initiation with induced skin chemical carcinogenesis. Further, CSCs isolated from the Sfrp1-/- tumors showed increased in vivo tumorigenic potential with enhanced tumor propagating cell (TPC) frequency when injected into NOD/SCID mice. Hence, in order to understand the molecular mechanism involved in CSC regulation in the absence of sfrp1, we have performed microarray analysis on CSCs isolated from mice skin SCC. The data showed upregulation of genes involved in the regulation of tumor aggressiveness, metastasis and stemness in Sfrp1-/- CSCs as compared to WT CSCs. Our study has provided significant contribution to the existing knowledge of Sfrp1 by showing the uncharted role of Sfrp1 in tumor initiation and CSC regulation.

ORGANISM(S): Mus musculus

PROVIDER: GSE141176 | GEO | 2020/01/30

REPOSITORIES: GEO

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Project description:Cancer stem cells (CSCs) have been reported in various cancers including skin squamous cell carcinoma (SCC). The molecular mechanisms regulating tumour initiation and stemness are still poorly characterized. Here, we found that Sox2, a transcription factor expressed in various types of embryonic and adult stem cells (SCs), was the most upregulated transcription factor in CSCs of squamous skin tumours. Sox2 is absent in normal epidermis and 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 dramatically decreases skin tumour formation following chemical induced carcinogenesis. Using Sox2-GFP knockin mice, we showed that Sox2 expressing cells in invasive SCC are greatly enriched in tumour propagating cells (TPCs) that 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 their regression and decreases their ability to be propagated upon transplantation into immunodeficient mice, supporting the essential role of Sox2 in regulating CSC functions. Transcriptional profiling of Sox2-GFP expressing CSC and 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. Altogether, our study demonstrates 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. We used microarrays to profile Sox2-GFP expressing CSC to uncover a gene network regulated by Sox2 in primary tumour cells in vivo. Two different biological replicates from SOX2-GFP+ and SOX2-GFP- TECs (control) from 2 different SCC from 2 different mice were analysed. Total RNA was analysed using Mouse whole genome 430 2.0 array from Affymetrix.

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Gene expression profile of cancer stem cells (CSCs) isolated from wild type (WT) and Sfrp1-/- mice skin squamous cell carcinoma (SCC)

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