Research ArticleCancer

MET signaling in keratinocytes activates EGFR and initiates squamous carcinogenesis

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Sci. Signal.  21 Jun 2016:
Vol. 9, Issue 433, pp. ra62
DOI: 10.1126/scisignal.aaf5106

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MET and RAS converge on EGFR in skin cancer

Whereas a subset of cutaneous melanomas harbor oncogenic mutations in N-RAS that lead to out-of-control signaling through this proliferative pathway, RAS mutations are infrequent in cutaneous squamous cell carcinomas (SCC). Cataisson et al. found that cutaneous SCC was associated with high amounts of hepatocyte growth factor (HGF), which activates the receptor MET. In transgenic mouse models, HGF and oncogenic RAS each activated a common downstream transcriptional program in skin cells, resulting in stimulation of the epidermal growth factor receptor (EGFR) pathway through the production and secretion of its ligands. Furthermore, established squamous tumors in mice regressed when this activation of or signaling by this EGFR pathway was blocked. In some human SCCs, high HGF and activated MET correlated with an EGFR-activating gene signature like the one identified in the mice, indicating that this pathway may offer therapeutic targets for patients.

Abstract

The receptor tyrosine kinase MET is abundant in many human squamous cell carcinomas (SCCs), but its functional significance in tumorigenesis is not clear. We found that the incidence of carcinogen-induced skin squamous tumors was substantially increased in transgenic MT-HGF (mouse metallothionein–hepatocyte growth factor) mice, which have increased abundance of the MET ligand HGF. Squamous tumors also erupted spontaneously on the skin of MT-HGF mice that were promoted by wounding or the application of 12-O-tetradecanoylphorbol 13-acetate, an activator of protein kinase C. Carcinogen-initiated tumors had Ras mutations, but spontaneous tumors did not. Cultured keratinocytes from MT-HGF mice and oncogenic RAS-transduced keratinocytes shared phenotypic and biochemical features of initiation that were dependent on autocrine activation of epidermal growth factor receptor (EGFR) through increased synthesis and release of EGFR ligands, which was mediated by the kinase SRC, the pseudoproteases iRhom1 and iRhom2, and the metallopeptidase ADAM17. Pharmacological inhibition of EGFR caused the regression of MT-HGF squamous tumors that developed spontaneously in orthografts of MT-HGF keratinocytes combined with dermal fibroblasts and implanted onto syngeneic mice. The global gene expression profile in MET-transformed keratinocytes was highly concordant with that in RAS-transformed keratinocytes, and a core RAS/MET coexpression network was activated in precancerous and cancerous human skin lesions. Tissue arrays revealed that many human skin SCCs have abundant HGF at both the transcript and protein levels. Thus, through the activation of EGFR, MET activation parallels a RAS pathway to contribute to human and mouse cutaneous cancers.

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