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 BrafV600E or KrasG12D 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.
Highlights
Melanoma patients treated with oncogenic BRAF inhibitors can develop cutaneous squamous cell carcinoma within weeks of treatment, driven by paradoxical RAS/RAF/mitogen-activated protein kinase (MAPK) pathway activation
Employing targeted deep sequencing of 39 squamo-proliferative lesions from seven patients (including cutaneous squamous cell carcinoma (cSCC) and actinic keratosis (Supplementary Table 1) treated with vemurafenib, we identified frequent coding mutations in both TGFBR1 (8/39, 21% of samples) and TGFBR2 (5/39, 13% of samples), revealing mutation of transforming growth factor-b (TGFb) receptors in 28% of lesions (Fig. 1a and Supplementary Data 1)
These findings imply that a combination of potential mutational inactivation of TGFb signalling and activation of HRAS may be important driving events in vemurafenib-induced skin lesions and skin tumorigenesis
Summary
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. We identify frequent TGFBR1 and TGFBR2 mutations in human vemurafenib-induced skin lesions and in sporadic cSCC Functional analysis reveals these mutations ablate canonical TGFb Smad signalling, which is localized to bulge stem cells in both normal human and murine skin. Mutation of Tp53 (which is commonly mutated in sporadic cSCC) coupled with Tgfbr[1] deletion in LGR5 þ ve cells results in cSCC development These findings indicate that LGR5 þ 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 TGFb signalling, are driving events of skin tumorigenesis. In murine skin, targeted activation of the RAS/RAF/mitogen-activated protein kinase (MAPK) pathway, coupled with deletion of Tgfbr[1] in LGR5 þ ve stem cells, promotes rapid development of cSCC, which, in the absence of wounding, may mimic the kinetics of tumour induction in vemurafenib-induced cSCC. Combined Tp53 mutation/inactivation coupled with Tgfbr[1] loss in LGR5 þ ve stem cells results in cSCC with longer latency, providing a model for cSCC development without RAS activation
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