Browsing The Manchester Institute Cancer Research UK by Authors
Frequent loss of function mutations in TGF beta R1 and TGF beta R2 implicate hair follicle bulge stem cells as a cell of origin of cutaneous squamous cell carcinoma.Cammareri, P; Rose, A; Vincent, D; Wang, J; Nagano, A; Libertini, S; Ridgway, R; McHugh, A; Pourreyron, C; Spender, L; et al. (2016)
Inactivation of TGFβ receptors in stem cells drives cutaneous squamous cell carcinoma.Cammareri, P; Rose, A; Vincent, D; Wang, J; Nagano, A; Libertini, S; Ridgway, R; Athineos, D; Coates, P; McHugh, A; et al. (2016-08-25)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.
Inactivation of transforming growth factor-beta receptors in human cutaneous squamous cell carcinoma and murine hair follicle stem cells drives tumorigenesis.Cammareri, P; Rose, A; Vincent, D; Wang, J; Nagano, A; Coates, P; Sapkota, G; Pudie, K; Proby, C; Harwood, C; et al. (2016)