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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 TGFβ receptors in stem cells drives cutaneous squamous cell carcinoma