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  • 1
    Publication Date: 2014-06-10
    Description: 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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Boumahdi, Soufiane -- Driessens, Gregory -- Lapouge, Gaelle -- Rorive, Sandrine -- Nassar, Dany -- Le Mercier, Marie -- Delatte, Benjamin -- Caauwe, Amelie -- Lenglez, Sandrine -- Nkusi, Erwin -- Brohee, Sylvain -- Salmon, Isabelle -- Dubois, Christine -- del Marmol, Veronique -- Fuks, Francois -- Beck, Benjamin -- Blanpain, Cedric -- England -- Nature. 2014 Jul 10;511(7508):246-50. doi: 10.1038/nature13305. Epub 2014 Jun 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Universite Libre de Bruxelles, IRIBHM, Brussels B-1070, Belgium. ; 1] Universite Libre de Bruxelles, IRIBHM, Brussels B-1070, Belgium [2]. ; 1] Department of Pathology, Erasme Hospital, Universite Libre de Bruxelles, Brussels B-1070, Belgium [2] DIAPATH-Center for Microscopy and Molecular Imaging (CMMI), Gosselies B-6041, Belgium. ; Department of Pathology, Erasme Hospital, Universite Libre de Bruxelles, Brussels B-1070, Belgium. ; Laboratory of Cancer Epigenetics, Universite Libre de Bruxelles, Brussels B-1070, Belgium. ; Machine Learning Group, Computer Science Department, Faculte des Sciences, Universite Libre de Bruxelles, Brussels B-1050, Belgium. ; Department of Dermatology, Erasme Hospital, Universite Libre de Bruxelles, Brussels B-1070, Belgium. ; 1] Universite Libre de Bruxelles, IRIBHM, Brussels B-1070, Belgium [2] WELBIO, Universite Libre de Bruxelles, Brussels B-1070, Belgium.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24909994" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Carcinoma, Squamous Cell/genetics/pathology ; Cell Adhesion/genetics ; Cell Proliferation ; Cell Transformation, Neoplastic/*genetics/metabolism ; Disease Models, Animal ; Gene Deletion ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Gene Knockdown Techniques ; Gene Regulatory Networks/genetics ; Mice ; Mice, Inbred Strains ; Neoplastic Stem Cells/*metabolism ; SOXB1 Transcription Factors/genetics/*metabolism ; *Skin Neoplasms/genetics/pathology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2015-08-13
    Description: Breast cancer is the most frequent cancer in women and consists of heterogeneous types of tumours that are classified into different histological and molecular subtypes. PIK3CA and P53 (also known as TP53) are the two most frequently mutated genes and are associated with different types of human breast cancers. The cellular origin and the mechanisms leading to PIK3CA-induced tumour heterogeneity remain unknown. Here we used a genetic approach in mice to define the cellular origin of Pik3ca-derived tumours and the impact of mutations in this gene on tumour heterogeneity. Surprisingly, oncogenic Pik3ca(H1047R) mutant expression at physiological levels in basal cells using keratin (K)5-CreER(T2) mice induced the formation of luminal oestrogen receptor (ER)-positive/progesterone receptor (PR)-positive tumours, while its expression in luminal cells using K8-CReER(T2) mice gave rise to luminal ER(+)PR(+) tumours or basal-like ER(-)PR(-) tumours. Concomitant deletion of p53 and expression of Pik3ca(H1047R) accelerated tumour development and induced more aggressive mammary tumours. Interestingly, expression of Pik3ca(H1047R) in unipotent basal cells gave rise to luminal-like cells, while its expression in unipotent luminal cells gave rise to basal-like cells before progressing into invasive tumours. Transcriptional profiling of cells that underwent cell fate transition upon Pik3ca(H1047R) expression in unipotent progenitors demonstrated a profound oncogene-induced reprogramming of these newly formed cells and identified gene signatures characteristic of the different cell fate switches that occur upon Pik3ca(H1047R) expression in basal and luminal cells, which correlated with the cell of origin, tumour type and different clinical outcomes. Altogether our study identifies the cellular origin of Pik3ca-induced tumours and reveals that oncogenic Pik3ca(H1047R) activates a multipotent genetic program in normally lineage-restricted populations at the early stage of tumour initiation, setting the stage for future intratumoural heterogeneity. These results have important implications for our understanding of the mechanisms controlling tumour heterogeneity and the development of new strategies to block PIK3CA breast cancer initiation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Van Keymeulen, Alexandra -- Lee, May Yin -- Ousset, Marielle -- Brohee, Sylvain -- Rorive, Sandrine -- Giraddi, Rajshekhar R -- Wuidart, Aline -- Bouvencourt, Gaelle -- Dubois, Christine -- Salmon, Isabelle -- Sotiriou, Christos -- Phillips, Wayne A -- Blanpain, Cedric -- England -- Nature. 2015 Sep 3;525(7567):119-23. doi: 10.1038/nature14665. Epub 2015 Aug 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Universite Libre de Bruxelles, IRIBHM, Brussels B-1070, Belgium. ; Institut Jules Bordet, Universite Libre de Bruxelles, Brussels B-1000, Belgium. ; Department of Pathology, Erasme Hospital, Universite Libre de Bruxelles, Brussels B-1070, Belgium. ; DIAPATH - Center for Microscopy and Molecular Imaging (CMMI), Gosselies B-6041, Belgium. ; Surgical Oncology Research Laboratory, Peter MacCallum Cancer Centre, Melbourne 3002, Australia. ; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville 3002, Australia. ; WELBIO, Universite Libre de Bruxelles, Brussels B-1070, Belgium.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26266985" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Breast Neoplasms/*genetics/metabolism/*pathology ; Cell Differentiation/genetics ; Cell Division ; Cell Lineage ; Cell Transformation, Neoplastic ; Female ; Genes, p53/genetics ; Humans ; Mammary Neoplasms, Animal/*genetics/metabolism/*pathology ; Mice ; Mutation/genetics ; Neoplasm Invasiveness/genetics ; Phenotype ; Phosphatidylinositol 3-Kinases/*genetics/metabolism ; Receptors, Estrogen/metabolism ; Receptors, Progesterone/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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