title: Defining the clonal dynamics leading to mouse skin tumour initiation.
abstract: The changes in cell dynamics after oncogenic mutation that lead to the development of tumours are currently unknown. Here, using skin epidermis as a model, we assessed the effect of oncogenic hedgehog signalling in distinct cell populations and their capacity to induce basal cell carcinoma, the most frequent cancer in humans. We found that only stem cells, and not progenitors, initiated tumour formation upon oncogenic hedgehog signalling. This difference was due to the hierarchical organization of tumour growth in oncogene-targeted stem cells, characterized by an increase in symmetric self-renewing divisions and a higher p53-dependent resistance to apoptosis, leading to rapid clonal expansion and progression into invasive tumours. Our work reveals that the capacity of oncogene-targeted cells to induce tumour formation is dependent not only on their long-term survival and expansion, but also on the specific clonal dynamics of the cancer cell of origin.
authors.forename: Adriana
authors.initials: A
authors.lastname: Sánchez-Danés
authors.forename: Edouard
authors.initials: E
authors.lastname: Hannezo
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Larsimont
authors.forename: Mélanie
authors.initials: M
authors.lastname: Liagre
authors.forename: Khalil Kass
authors.initials: KK
authors.lastname: Youssef
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Simons
authors.forename: Cédric
authors.initials: C
authors.lastname: Blanpain
mesh_terms: D000818:Animals; D017209:Apoptosis; D002280:Basal Cell Carcinoma / Q000235:genetics / Q000473:pathology*; D000066673:Cell Self Renewal; D002470:Cell Survival; D002999:Clone Cells / Q000473:pathology*; D018450:Disease Progression; D004817:Epidermis / Q000473:pathology; D005260:Female; D053823:Hedgehog Proteins / Q000378:metabolism; D006706:Homeostasis; D008297:Male; D051379:Mice; D009154:Mutation / Q000235:genetics; D014411:Neoplastic Stem Cells / Q000473:pathology*; D009857:Oncogenes / Q000235:genetics; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000235:genetics / Q000473:pathology*; D013623:Tail / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D053823:Hedgehog Proteins; D016159:Tumor Suppressor Protein p53