Defining the clonal dynamics leading to mouse skin tumour initiation

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. Skin stem cells, but not their progenitors, are able to form tumours owing to the ability of oncogene-targeted stem cells to increase symmetric self-renewing division and a higher p53-dependent resistance to apoptosis. This paper presents a quantitative analysis of tumour intiation, from the first oncogenic event to the development of invasive tumours. Cédric Blanpain and colleagues introduced the same oncogenic alterations — oncogenic hedgehog (HH) signalling — into distinct skin epidermis cell populations and measured their capacity to induce basal cell carcinomas. Only skin stem cells, and not their progenitors, were able to form tumours. The difference is due to the ability of oncogene-targeted stem cells to increase symmetric self-renewing divisions, and a higher p53-dependent resistance to apoptosis.