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https://doi.org/10.1038/ncomms12493
| Title: | Inactivation of TGF? receptors in stem cells drives cutaneous squamous cell carcinoma | 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 Inman, G.J |
Keywords: | B Raf kinase K ras protein mitogen activated protein kinase Smad2 protein Smad3 protein Smad4 protein transforming growth factor beta receptor 1 transforming growth factor beta receptor 2 antineoplastic agent B Raf kinase indole derivative protein p21 protein p53 protein serine threonine kinase sulfonamide TGF-beta type I receptor transforming growth factor beta transforming growth factor beta receptor transforming growth factor-beta type II receptor vemurafenib cancer cells and cell components cytology gene genetic engineering mutation protein rodent skin tumor animal experiment animal model animal tissue Article controlled study disease course extracellular matrix female gene mutation human human tissue male mouse nonhuman signal transduction skin carcinogenesis skin carcinoma stem cell animal antagonists and inhibitors biopsy carcinogenesis chemically induced dna mutational analysis drug effect experimental neoplasm genetics inbred mouse strain melanoma metabolism mutation pathology procedures skin tumor squamous cell carcinoma stem cell tumor cell line whole exome sequencing Murinae Animals Antineoplastic Agents Biopsy Carcinogenesis Carcinoma, Squamous Cell Cell Line, Tumor DNA Mutational Analysis Female Humans Indoles Male Melanoma Mice Mice, Inbred Strains Mutation Neoplasms, Experimental Protein-Serine-Threonine Kinases Proto-Oncogene Proteins B-raf Proto-Oncogene Proteins p21(ras) Receptors, Transforming Growth Factor beta Signal Transduction Skin Neoplasms Stem Cells Sulfonamides Transforming Growth Factor beta Tumor Suppressor Protein p53 Whole Exome Sequencing |
Issue Date: | 2016 | Publisher: | Nature Publishing Group | Citation: | 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, Inman, G.J (2016). Inactivation of TGF? receptors in stem cells drives cutaneous squamous cell carcinoma. Nature Communications 7 : 12493. ScholarBank@NUS Repository. https://doi.org/10.1038/ncomms12493 | Rights: | Attribution 4.0 International | 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 TGF? 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 TGF? 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 TGF? signalling, are driving events of skin tumorigenesis. © The Author(s) 2016. | Source Title: | Nature Communications | URI: | https://scholarbank.nus.edu.sg/handle/10635/182434 | ISSN: | 2041-1723 | DOI: | 10.1038/ncomms12493 | Rights: | Attribution 4.0 International |
| Appears in Collections: | Elements Staff Publications |
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