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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / adverse effects*
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Biopsy
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Carcinogenesis / genetics
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Carcinoma, Squamous Cell / chemically induced*
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Carcinoma, Squamous Cell / genetics*
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Carcinoma, Squamous Cell / pathology
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Cell Line, Tumor
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DNA Mutational Analysis / methods
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Exome Sequencing
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Female
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Humans
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Indoles / adverse effects
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Male
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Melanoma / drug therapy*
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Mice
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Mice, Inbred Strains
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Mutation
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Neoplasms, Experimental / chemically induced
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Neoplasms, Experimental / genetics
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Neoplasms, Experimental / pathology
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Protein Serine-Threonine Kinases / genetics*
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Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
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Proto-Oncogene Proteins B-raf / genetics
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Proto-Oncogene Proteins B-raf / metabolism
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Proto-Oncogene Proteins p21(ras) / genetics
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Proto-Oncogene Proteins p21(ras) / metabolism
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Receptor, Transforming Growth Factor-beta Type I
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Receptor, Transforming Growth Factor-beta Type II
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Receptors, Transforming Growth Factor beta / genetics*
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Signal Transduction / drug effects
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Skin Neoplasms / chemically induced*
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Skin Neoplasms / genetics*
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Skin Neoplasms / pathology
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Stem Cells
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Sulfonamides / adverse effects
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Transforming Growth Factor beta / metabolism
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Tumor Suppressor Protein p53 / genetics
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Vemurafenib
Substances
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Antineoplastic Agents
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Indoles
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Receptors, Transforming Growth Factor beta
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Sulfonamides
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Transforming Growth Factor beta
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Tumor Suppressor Protein p53
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Vemurafenib
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins B-raf
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Receptor, Transforming Growth Factor-beta Type I
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Receptor, Transforming Growth Factor-beta Type II
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TGFBR1 protein, human
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Tgfbr1 protein, mouse
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Proto-Oncogene Proteins p21(ras)