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

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, Jasbani H. S. Dayal, Jonas Larsson, Simone Weidlich, Lindsay C. Spender, Gopal P. Sapkota, Karin J. Purdie, Charlotte M. Proby, Catherine A. Harwood, Irene M. Leigh, Hans Clevers, Nick Barker, Stefan Karlsson, Catrin Pritchard, Richard Marais, Claude Chelala, Andrew P. South, Owen J. Sansom () and Gareth J. Inman ()
Additional contact information
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
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
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

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: 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.

Date: 2016
References: Add references at CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/ncomms12493 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms12493

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/ncomms12493

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().