MET signaling in keratinocytes activates EGFR and initiates squamous carcinogenesis

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 metallothioneinhepatocyte 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.

Cell autonomous or systemic EGFR blockade alters the immune‐environment in squamous cell carcinomas

“…Signaling downstream from oncogenic RAS is dependent on an intact EGFR in mouse keratinocytes. 10 Accordingly, in the genetic model, tumor growth was consistently impaired by the absence of EGFR in tumor epithelium ( Fig. 1a).…”

“…Both groups were transformed with a constitutively active form of HRAS that is expressed equally in both genotypes (Suppl Fig.1a). Signaling downstream from oncogenic RAS is dependent on an intact EGFR in mouse keratinocytes 10 . Accordingly, in the genetic model, tumor growth was consistently impaired by the absence of EGFR in tumor epithelium (Fig.…”

A Constitutional Activating MET Mutation Makes the Genetic Link between Malignancies and Chronic Inflammatory Diseases

“…We did not reproduce spontaneous breast or thyroid cancers, but the systematic pathologic study found lymphocytic thyroiditis in 14 of 23 transgenic mice when, in patients, chronic lymphocytic thyroiditis is associated with a 2-fold increased risk of papillary thyroid cancer (39). In addition, one of the transgenic mice developed a skin squamous cell carcinoma of the ear, as observed in mice transgenic for HGF with a strong activation of the MET pathway (40). We reproduced experimentally the occurrence of skin carcinomas in our transgenic mice, and reduced significantly the number of cancers by concomitant administration of a MET inhibitor demonstrating that MET activation is sufficient for increasing the susceptibility to skin cancer.…”

The Identification of Potential Therapeutic Targets for Cutaneous Squamous Cell Carcinoma

“…We observed that directly targeting MET, EGFR, or ERBB2 was sufficient to impact cSCC cell viability (Figure 3c). MET and EGFR/ERBB2 signaling pathways can contribute to driving cSCC development, and a subset of cSCCs respond to EGFR inhibitors (Cataisson et al, 2016;Harwood et al, 2016;Mellerio et al, 2016). Suppression of USP8 could provide a means to simultaneously interfere with multiple therapeutically relevant receptors, which could overcome resistance because of receptor redundancy or cross-talk.…”