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

Author

Listed:
  • Patrizia Cammareri

    (Wnt Signaling and Colorectal Cancer Group, Cancer Research UK Beatson Institute, Institute of Cancer Sciences, Glasgow University)

  • Aidan M. Rose

    (School of Medicine, University of Dundee)

  • David F. Vincent

    (Wnt Signaling and Colorectal Cancer Group, Cancer Research UK Beatson Institute, Institute of Cancer Sciences, Glasgow University)

  • Jun Wang

    (Bioinformatics Unit, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square)

  • Ai Nagano

    (Bioinformatics Unit, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square)

  • Silvana Libertini

    (Wnt Signaling and Colorectal Cancer Group, Cancer Research UK Beatson Institute, Institute of Cancer Sciences, Glasgow University)

  • Rachel A. Ridgway

    (Wnt Signaling and Colorectal Cancer Group, Cancer Research UK Beatson Institute, Institute of Cancer Sciences, Glasgow University)

  • Dimitris Athineos

    (Wnt Signaling and Colorectal Cancer Group, Cancer Research UK Beatson Institute, Institute of Cancer Sciences, Glasgow University)

  • Philip J. Coates

    (Tayside Tissue Bank, School of Medicine, University of Dundee)

  • Angela McHugh

    (School of Medicine, University of Dundee)

  • Celine Pourreyron

    (School of Medicine, University of Dundee)

  • Jasbani H. S. Dayal

    (School of Medicine, University of Dundee)

  • Jonas Larsson

    (Molecular Medicine and Gene Therapy, Lund Strategic Center for Stem Cell Biology, Lund University)

  • Simone Weidlich

    (MRC Protein Phosphorylation Unit, School of Life Sciences, University of Dundee)

  • Lindsay C. Spender

    (School of Medicine, University of Dundee)

  • Gopal P. Sapkota

    (MRC Protein Phosphorylation Unit, School of Life Sciences, University of Dundee)

  • Karin J. Purdie

    (Centre for Cutaneous Research, Barts and the London School of Medicine and Dentistry, Queen Mary University of London)

  • Charlotte M. Proby

    (School of Medicine, University of Dundee)

  • Catherine A. Harwood

    (Centre for Cutaneous Research, Barts and the London School of Medicine and Dentistry, Queen Mary University of London)

  • Irene M. Leigh

    (School of Medicine, University of Dundee
    Centre for Cutaneous Research, Barts and the London School of Medicine and Dentistry, Queen Mary University of London)

  • Hans Clevers

    (Hubrecht Institute)

  • Nick Barker

    (Institute of Medical Biology)

  • Stefan Karlsson

    (Molecular Medicine and Gene Therapy, Lund Strategic Center for Stem Cell Biology, Lund University)

  • Catrin Pritchard

    (University of Leicester)

  • Richard Marais

    (The Paterson Institute for Cancer Research)

  • Claude Chelala

    (Bioinformatics Unit, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square)

  • Andrew P. South

    (School of Medicine, University of Dundee
    Thomas Jefferson University)

  • Owen J. Sansom

    (Wnt Signaling and Colorectal Cancer Group, Cancer Research UK Beatson Institute, Institute of Cancer Sciences, Glasgow University)

  • Gareth J. Inman

    (School of Medicine, University of Dundee)

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.

Suggested Citation

  • Patrizia Cammareri & Aidan M. Rose & David F. Vincent & Jun Wang & Ai Nagano & Silvana Libertini & Rachel A. Ridgway & Dimitris Athineos & Philip J. Coates & Angela McHugh & Celine Pourreyron & Jasban, 2016. "Inactivation of TGFβ receptors in stem cells drives cutaneous squamous cell carcinoma," Nature Communications, Nature, vol. 7(1), pages 1-14, November.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms12493
    DOI: 10.1038/ncomms12493
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    Cited by:

    1. Peter Bailey & Rachel A. Ridgway & Patrizia Cammareri & Mairi Treanor-Taylor & Ulla-Maja Bailey & Christina Schoenherr & Max Bone & Daniel Schreyer & Karin Purdie & Jason Thomson & William Rickaby & R, 2023. "Driver gene combinations dictate cutaneous squamous cell carcinoma disease continuum progression," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

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