Inactivation of TGFβ receptors in stem cells drives cutaneous squamous cell carcinoma

Patrizia Cammareri, Aidan Rose, David F. Vincent, Jun Wang, Ai Nagano, Silvana Libertini, Rachel A. Ridgway, Dimitris Athineos, Philip J . Coates, Angela McHugh, Celine Pourreyron, Jasbani Dayal, Jonas Larsson, Simone Weidlich, Lindsay Spender, Gopal Sapkota, Karin J. Purdie, Charlotte Proby, Catherine A. Harwood, Irene LeighHans Clevers, Nick Barker, Stefan Karlsson, Catrin Pritchard, Richard Marais, Claude Chelala, Andrew South, Owen J. Sansom, Gareth Inman

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Abstract

Melanoma patients treated with oncogenic BRAF inhibitors can develop cutaneous squamous cell carcinoma (cSCC) within weeks of treatment, driven by paradoxical RAS/RAF MAPK pathway activation. Here, we identify frequent TGFBR1 and TGFBR2 mutations in human vemurafenib-induced skin lesions and in sporadic cSCC. Functional analysis reveals these mutations ablate canonical TGFb Smad signaling which is localised to bulge stem cells in both normal human and murine skin. MAPK pathway hyperactivation (through BRafV600E or KRASG12D knockin) and TGFb signaling ablation (through Tgfbr1 deletion) in Lgr5+ve stem cells enables rapid cSCC development in the mouse. Mutation of TP53 (which is commonly mutated in sporadic cSCC) coupled with TGFbR1 deletion in Lgr5+ve cells also results in cSCC development. These findings indicate that Lgr5+ve stem cells can act as a cell of origin for cSCC and that RAS-RAF-MAPK pathway hyperactivation or TP53 mutation, coupled with loss of TGFb signaling, are driving events of skin tumorigenesis.
Original languageEnglish
Article number12493
Pages (from-to)1-7
Number of pages7
JournalNature Communications
Volume7
DOIs
Publication statusPublished - 25 Aug 2016

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    Cite this

    Cammareri, P., Rose, A., Vincent, D. F., Wang, J., Nagano, A., Libertini, S., Ridgway, R. A., Athineos, D., Coates, P. J. ., McHugh, A., Pourreyron, C., Dayal, J., Larsson, J., Weidlich, S., Spender, L., Sapkota, G., Purdie, K. J., Proby, C., Harwood, C. A., ... Inman, G. (2016). Inactivation of TGFβ receptors in stem cells drives cutaneous squamous cell carcinoma. Nature Communications, 7, 1-7. [12493]. https://doi.org/10.1038/ncomms12493