Defining the clonal dynamics leading to mouse skin tumour initiation
Youssef, Khalil Kass
Nature Publishing Group
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Sánchez-Danés, A., Hannezo, E., Larsimont, J., Liagre, M., Youssef, K. K., Simons, B., & Blanpain, C. (2016). Defining the clonal dynamics leading to mouse skin tumour initiation. Nature https://doi.org/10.1038/nature19069
The changes that occur in cell dynamics following oncogenic mutation that lead to the development of tumours are currently unknown. Here, using skin epidermis as a model, we assessed the impact 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, were competent to initiate tumour formation upon oncogenic hedgehog signalling. Interestingly, 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.
basal cell carcinoma, cancer stem cells
C.B. is an investigator of WELBIO. A.S-D. and JC.L. are supported by a fellowship of the FNRS and FRIA respectively. B.D.S. and E.H. are supported by the Wellcome Trust (grant number 098357/Z/12/Z and 110326/Z/15/Z). EH is supported by a fellowship from Trinity College, Cambridge. This work was supported by the FNRS, the IUAP program, the Fondation contre le Cancer, the ULB fondation, the foundation Bettencourt Schueller, the foundation Baillet Latour, a consolidator grant of the European Research Council.
Wellcome Trust (098357/Z/12/Z)
WELLCOME TRUST (110326/Z/15/Z)
External DOI: https://doi.org/10.1038/nature19069
This record's URL: https://www.repository.cam.ac.uk/handle/1810/257286