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)

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 Wang, Dr Jun and Vincent, Dr David and Athineos, Mr Dimitris and Ridgway, Dr Rachel and Inman, Professor Gareth 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 > School of Cancer Sciences; College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: Nature Communications
• Publisher: Nature Publishing Group
• ISSN: 2041-1723
• ISSN (Online): 2041-1723
• Copyright Holders: Copyright © 2016 The Authors
• First Published: First published in Nature Communications 7: 12493
• Publisher Policy: Reproduced under a Creative Commons License