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Identification of the cell lineage at the origin of basal cell carcinoma

Abstract

For most types of cancers, the cell at the origin of tumour initiation is still unknown. Here, we used mouse genetics to identify cells at the origin of basal cell carcinoma (BCC), which is one of the most frequently occurring types of cancer in humans, and can result from the activation of the Hedgehog signalling pathway. Using mice conditionally expressing constitutively active Smoothened mutant (SmoM2), we activated Hedgehog signalling in different cellular compartments of the skin epidermis and determined in which compartments Hedgehog activation induces BCC formation. Activation of SmoM2 in hair follicle bulge stem cells and their transient amplifying progenies did not induce cancer formation, demonstrating that BCC does not originate from bulge stem cells, as previously thought. Using clonal analysis, we found that BCC arises from long-term resident progenitor cells of the interfollicular epidermis and the upper infundibulum. Our studies uncover the cells at the origin of BCC in mice and demonstrate that expression of differentiation markers in tumour cells is not necessarily predictive of the cancer initiating cells.

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Figure 1: BCCs do not arise from hair follicle bulge stem cells and their progenies.
Figure 2: BCC originates from cells residing in the interfollicular epidermis and the infundibulum.
Figure 3: BCC does not arise from Shh-derived hair follicle and infundibulum cells.
Figure 4: BCC originates from long-lived resident progenitor cells of the interfollicular epidermis.
Figure 5: Model of BCC initiation in adult mice.

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Acknowledgements

We thank our colleagues who provided reagents, and whose gifts are cited in the text. We thank C. Govaerts, H. Nguyen, P. Vanderhaeghen and G. Vassart for their critical comments on the manuscript. C.B. and A.V.K. are Chercheur Qualifie of the FRS/FNRS; K.K.Y is a Research Fellow of the FRIA; and G.L. is Collaborateur Scientifique of the FRS/FNRS. This work was supported by a Mandat D'impulsion Scientifique of the FNRS, a career development award of the Human Frontier Science Program Organization, a research grant of the Schlumberger Foundation, the programme CIBLES of the Wallonia Region, the EMBO Young Investigator program and from a starting grant of the European Research Council.

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Correspondence to Cédric Blanpain.

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Youssef, K., Van Keymeulen, A., Lapouge, G. et al. Identification of the cell lineage at the origin of basal cell carcinoma. Nat Cell Biol 12, 299–305 (2010). https://doi.org/10.1038/ncb2031

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