title: Inactivation of TGFβ receptors in stem cells drives cutaneous squamous cell carcinoma.
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 Braf(V600E) or Kras(G12D) 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.
authors: Wnt Signaling and Colorectal Cancer Group, Cancer Research UK Beatson Institute, Institute of Cancer Sciences, Glasgow University, Garscube Estate, Switichback Road, Glasgow G61 1BD, UK.
authors: Patrizia
authors: P
authors: Cammareri
authors: Division of Cancer Research, School of Medicine, University of Dundee, Dundee DD1 9SY, UK.
authors: Aidan M
authors: AM
authors: Rose
authors: Wnt Signaling and Colorectal Cancer Group, Cancer Research UK Beatson Institute, Institute of Cancer Sciences, Glasgow University, Garscube Estate, Switichback Road, Glasgow G61 1BD, UK.
authors: David F
authors: 0000-0001-6482-8040
authors: DF
authors: Vincent
authors: Bioinformatics Unit, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
authors: Jun
authors: J
authors: Wang
authors: Bioinformatics Unit, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
authors: Ai
authors: A
authors: Nagano
authors: Wnt Signaling and Colorectal Cancer Group, Cancer Research UK Beatson Institute, Institute of Cancer Sciences, Glasgow University, Garscube Estate, Switichback Road, Glasgow G61 1BD, UK.
authors: Silvana
authors: S
authors: Libertini
authors: Wnt Signaling and Colorectal Cancer Group, Cancer Research UK Beatson Institute, Institute of Cancer Sciences, Glasgow University, Garscube Estate, Switichback Road, Glasgow G61 1BD, UK.
authors: Rachel A
authors: RA
authors: Ridgway
authors: Wnt Signaling and Colorectal Cancer Group, Cancer Research UK Beatson Institute, Institute of Cancer Sciences, Glasgow University, Garscube Estate, Switichback Road, Glasgow G61 1BD, UK.
authors: Dimitris
authors: 0000-0001-5298-7941
authors: D
authors: Athineos
authors: Tayside Tissue Bank, School of Medicine, University of Dundee, Dundee DD1 9SY, UK.
authors: Philip J
authors: PJ
authors: Coates
authors: Division of Cancer Research, School of Medicine, University of Dundee, Dundee DD1 9SY, UK.
authors: Angela
authors: A
authors: McHugh
authors: Division of Cancer Research, School of Medicine, University of Dundee, Dundee DD1 9SY, UK.
authors: Celine
authors: C
authors: Pourreyron
authors: Division of Cancer Research, School of Medicine, University of Dundee, Dundee DD1 9SY, UK.
authors: Jasbani H S
authors: JH
authors: Dayal
authors: Molecular Medicine and Gene Therapy, Lund Strategic Center for Stem Cell Biology, Lund University, Lund 221 00, Sweden.
authors: Jonas
authors: J
authors: Larsson
authors: MRC Protein Phosphorylation Unit, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
authors: Simone
authors: S
authors: Weidlich
authors: Division of Cancer Research, School of Medicine, University of Dundee, Dundee DD1 9SY, UK.
authors: Lindsay C
authors: LC
authors: Spender
authors: MRC Protein Phosphorylation Unit, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
authors: Gopal P
authors: GP
authors: Sapkota
authors: Centre for Cutaneous Research, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
authors: Karin J
authors: KJ
authors: Purdie
authors: Division of Cancer Research, School of Medicine, University of Dundee, Dundee DD1 9SY, UK.
authors: Charlotte M
authors: CM
authors: Proby
authors: Centre for Cutaneous Research, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
authors: Catherine A
authors: CA
authors: Harwood
authors: Division of Cancer Research, School of Medicine, University of Dundee, Dundee DD1 9SY, UK.|Centre for Cutaneous Research, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
authors: Irene M
authors: IM
authors: Leigh
authors: Hubrecht Institute, Utrecht 3584 CT, The Netherlands.
authors: Hans
authors: H
authors: Clevers
authors: Institute of Medical Biology, Immunos 138648, Singapore.
authors: Nick
authors: N
authors: Barker
authors: Molecular Medicine and Gene Therapy, Lund Strategic Center for Stem Cell Biology, Lund University, Lund 221 00, Sweden.
authors: Stefan
authors: S
authors: Karlsson
authors: Department of Biochemistry, University of Leicester, Leicester LE1 9HN, UK.
authors: Catrin
authors: C
authors: Pritchard
authors: The Paterson Institute for Cancer Research, Manchester M20 4BX, UK.
authors: Richard
authors: 0000-0001-7484-4183
authors: R
authors: Marais
authors: Bioinformatics Unit, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
authors: Claude
authors: C
authors: Chelala
authors: Division of Cancer Research, School of Medicine, University of Dundee, Dundee DD1 9SY, UK.|Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
authors: Andrew P
authors: AP
authors: South
authors: Wnt Signaling and Colorectal Cancer Group, Cancer Research UK Beatson Institute, Institute of Cancer Sciences, Glasgow University, Garscube Estate, Switichback Road, Glasgow G61 1BD, UK.
authors: Owen J
authors: 0000-0001-9540-3010
authors: OJ
authors: Sansom
authors: Division of Cancer Research, School of Medicine, University of Dundee, Dundee DD1 9SY, UK.
authors: Gareth J
authors: GJ
authors: Inman
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D001706:Biopsy; D063646:Carcinogenesis / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced* / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D006801:Humans; D007211:Indoles / Q000009:adverse effects; D008297:Male; D008545:Melanoma / Q000188:drug therapy*; D051379:Mice; D008815:Mice, Inbred Strains; D009154:Mutation; D009374:Neoplasms, Experimental / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000235:genetics* / Q000473:pathology; D013234:Stem Cells; D013449:Sulfonamides / Q000009:adverse effects; D016212:Transforming Growth Factor beta / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D000077484:Vemurafenib; D000073359:Exome Sequencing
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D018125:Receptors, Transforming Growth Factor beta; D013449:Sulfonamides; D016212:Transforming Growth Factor beta; D016159:Tumor Suppressor Protein p53; D000077484:Vemurafenib; D017346:Protein Serine-Threonine Kinases; D048493:Proto-Oncogene Proteins B-raf; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; C000625841:TGFBR1 protein, human; C000625842:Tgfbr1 protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)