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

Cammareri, P. et al. (2016) Inactivation of TGFβ receptors in stem cells drives cutaneous squamous cell carcinoma. Nature Communications, 7, 12493. (doi:10.1038/ncomms12493) (PMID:27558455) (PMCID:PMC5007296)

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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 TGFβ Smad signalling, which is localized to bulge stem cells in both normal human and murine skin. MAPK pathway hyperactivation (through BrafV600E or KrasG12D knockin) and TGFβ signalling 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 may act as cells of origin for cSCC, and that RAS/RAF/MAPK pathway hyperactivation or Tp53 mutation, coupled with loss of TGFβ signalling, are driving events of skin tumorigenesis.

Item Type:Articles
Additional Information:O.S. is supported by a Cancer Research UK core grant (A21139) and an ERC starting grant (311301). P.C. is supported by FP7 Health CP-IP - Large-scale integrating project grant (278568). D.F.V. is supported by ERC Starting grant (311301). A.M.R. is supported by Cancer Research UK centre grant (A12976). L.C.S. was supported by WWCR grant 11-0788. G.J.I. was supported by WWCR fellowship (03-0900). G.J.I., I.M.L., C.M.P., C.A.H., K.J.P., A.M., C.P. and A.P.S. were supported by a Cancer Research UK programme grant (A13044) and an ERC grant (250170). J.W., A.N. and C.C. were supported by a Cancer Research UK centre award to Barts Cancer Institute.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Spender, Dr Lindsay and Cammareri, Dr Patrizia and Ridgway, Dr Rachel and Inman, Professor Gareth and Wang, Dr Jun and Vincent, Dr David and Athineos, Mr Dimitris and Sansom, Professor Owen and Libertini, Dr Silvana
Authors: Cammareri, P., Rose, A. M., Vincent, D. F., Wang, J., Nagano, A., Libertini, S., Ridgway, R. A., Athineos, D., Coates, P. J., McHugh, A., Pourreyron, C., Dayal, J. H.S., Larsson, J., Weidlich, S., Spender, L. C., Sapkota, G. P., Purdie, K. J., Proby, C. M., Harwood, C. A., Leigh, I. M., Clevers, H., Barker, N., Karlsson, S., Pritchard, C., Marais, R., Chelala, C., South, A. P., Sansom, O. J., and Inman, G. J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Nature Communications
Publisher:Nature Publishing Group
ISSN:2041-1723
ISSN (Online):2041-1723
Published Online:25 August 2016
Copyright Holders:Copyright © 2016 The Authors
First Published:First published in Nature Communications 7: 12493
Publisher Policy:Reproduced under a Creative Commons License

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