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Stem cells in epithelial cancer initiation and growth

Final Report Summary - CANCERSTEM (Stem cells in epithelial cancer initiation and growth)


The ERC CancerStem project aims at defining the role of stem and progenitor cells during skin cancer initiation and the role of cancer stem cells in regulating tumor growth and progression.

For the vast majority of cancers, the cell at the origin of tumor initiation is still unknown. Using mouse model of basal cell carcinoma (BCC) induced by smoothened mutant expression, we found that BCC arise from long-lived SCs of the interfollicular epidermis (Cover of Nature Cell Biology 2010 accompanied by a preview published in Cell Stem Cell). By transcriptional profiling, oncogene expressing cells at different stages of tumor progression, we found that BCC initiating cells are reprogrammed into embryonic hair follicle progenitors during tumor initiation. (Nature Cell Biology 2012 highlighted by a news and views in Nature cell Biology). Squamous cell carcinoma represents the second most frequent skin cancer. Using mice conditionally expressing a constitutively active KRas mutant and an inducible CRE in different epidermal lineages, we found that different epidermal lineages including bulge SC are competent to initiate papilloma formation and multiple genetic hits in the context of oncogenic KRas are required for the development of invasive SCC (PNAS (2011), highlighted by a preview in Nature Medicine).

Using novel lineage tracing and clonal analysis in mice, we found that long-lived SCs contribute to the long-term repair of the epidermis and rapidly cycling progenitors ensures the daily maintenance of the epidermis (Nature 2012 and highlighted by a news and views in Nature and Nature Reviews Molecular and Cellular Biology). We found that the different mammary epithelium lineages are self-sustained after birth by distinct lineage restricted unipotent stem cells. (Nature 20119 highlighted by a preview in Nature Cell Biology, Cell Stem Cell, and EMBO J) while different population of multipotent basal cells and unipotent basal and luminal progenitors mediate prostate development. (Nature Cell Biology 2012 highlighted by a preview in EMBO Reports) .

Little is known about how adult stem cells maintain their genomic integrity, sense and respond to DNA damage within their natural niche to restrain tumor initiation. We found that adult bulge SCs are very resistant to DNA damage-induced cell death due to an elevated expression of Bcl2 and an accelerated DNA repair activity (Nature Cell Biology 2010 and highlighted in Nature Reviews Molecular and Cellular Biology) and found that Brca1, a key mediator of DNA repair, is essential for the specification and the renewal of hair follicle stem cells (Cover of Genes and Development 2013)

Cancer stem cells (CSCs) have been described in many different mouse and human cancers including squamous tumours of the skin. Cancer stem cell potential are usually assessed by the ability of cancer cells to propagate the tumor upon transplantation into immunodeficient mice. We found that in skin squamous tumors, tumor propagating frequency increased with tumor progression, invasiveness and serial transplantation (EMBO Journal 2012 highlighted in Nature Reviews Cancer). To assess the fate of tumor cells in their natural environment during tumor growth, we performed for the first time clonal analysis to unravel the mode of tumour growth and provide the first experimental evidence for the existence of CSC during unperturbed solid tumour growth in vivo (Nature 201220 highlighted in Nature, Science, Nature Biotech, Nature Methods, Nature Reviews Cancer, and Science and Business exchange). Using genetic gain and loss of VEGF function in mice, we uncovered a dual role for VEGF in regulating skin tumor stemness. In one hand, the secretion of VEGF by tumor cells stimulates neoangiogenesis, which create a vascular niche for CSCs. On the other hand, VEGF acts directly on tumor cells in an autocrine loop through a Nrp1 dependent mechanism to promote CSC renewal and tumour growth ( Nature 2011 highlighted in Nature, Nature Biotech, Nature Reviews Cancer, and Science and Business exchange).