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

Cammareri, Patrizia; Rose, Aidan M.; Vincent, David F.; Wang, Jun; Nagano, Ai; Libertini, Silvana; Ridgway, Rachel A.; Athineos, Dimitris; Coates, Philip J. and McHugh, Angela, et al. (2016) In Nature Communications 7.
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... (More)

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.

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@article{566613de-909e-4bcc-a755-0731e8ca92c9,
  abstract     = {<p>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.</p>},
  articleno    = {12493},
  author       = {Cammareri, Patrizia and Rose, Aidan M. and Vincent, David F. and Wang, Jun and Nagano, Ai and Libertini, Silvana and Ridgway, Rachel A. and Athineos, Dimitris and Coates, Philip J. and McHugh, Angela and Pourreyron, Celine and Dayal, Jasbani H S and Larsson, Jonas and Weidlich, Simone and Spender, Lindsay C. and Sapkota, Gopal P. and Purdie, Karin J. and Proby, Charlotte M. and Harwood, Catherine A. and Leigh, Irene M. and Clevers, Hans and Barker, Nick and Karlsson, Stefan and Pritchard, Catrin and Marais, Richard and Chelala, Claude and South, Andrew P. and Sansom, Owen J. and Inman, Gareth J.},
  issn         = {2041-1723},
  language     = {eng},
  month        = {08},
  publisher    = {Nature Publishing Group},
  series       = {Nature Communications},
  title        = {Inactivation of TGFβ receptors in stem cells drives cutaneous squamous cell carcinoma},
  url          = {http://dx.doi.org/10.1038/ncomms12493},
  volume       = {7},
  year         = {2016},
}