Germline Met Mutations in Mice Reveal Mutation- and Background-Associated Differences in Tumor Profiles

Abstract

BackgroundThe receptor tyrosine kinase Met is involved in the progression and metastasis of numerous human cancers. Although overexpression and autocrine activation of the Met signaling pathway are commonly found in human cancers, mutational activation of Met has been observed in small cell and non-small cell lung cancers, lung adenocarcinomas, renal carcinomas, and mesotheliomas.Methodology/Principal FindingsTo investigate the influence of mutationally activated Met in tumorigenesis, we utilized a novel mouse model. Previously, we observed that various Met mutations developed unique mutation-specific tumor spectra on a C57BL/6 background. Here, we assessed the effect of genetic background on the tumorigenic potential of mutationally activated Met. For this purpose, we created congenic knock-in lines of the Met mutations D1226N, M1248T, and Y1228C on the FVB/N background. Consistent with the mutation-specific tumor spectra, several of the mutations were associated with the same tumor types as observed on C57BL/6 background. However, on the FVB/N background most developed a high incidence of mammary carcinomas with diverse histopathologies.Conclusions/SignificanceThis study demonstrates that on two distinct mouse backgrounds, Met is able to initiate tumorigenesis in multiple cell types, including epithelial, hematopoietic, and endothelial. Furthermore, these observations emphasize that even a modest increase in Met activation can initiate tumorigenesis with both the Met mutational spectra and host background having profound influence on the type of tumor generated. Greater insight into the interaction of genetic modifiers and Met signaling will significantly enhance our ability to tailor combination therapies for Met-driven cancers.

MET in human cancer: germline and somatic mutations

“…Even though the knock-in mutation models never developed renal carcinomas, when placed on an FVB/N background, each Met mutant (except for D1226N) developed aggressive mammary carcinomas (11). Again, unique mammary carcinoma phenotypes were observed between the M1248T, Y1228C, and M1248T/L1193V lines (12). Since the only differences between these animals were the Met mutations and the murine background strain, this study indicated that either the mutated kinase structure itself or the level of kinase they impose (or both) influence the tissue-specificity for tumor formation.…”

Cancer Genes in Lung Cancer: Racial Disparities: Are There Any?

“…Interestingly, preclinical studies in germline met mutations in a murine transgenic model reveal mutation- and background-associated differences in tumor profiles. 90 The most frequently detected MET mutation, N375S, occurred in 13% of East Asians compared to only 2.6% in whites and none among African Americans. MET mutations were also more likely to exist in male smokers and squamous cell carcinoma.…”

Anti-MET Targeted Therapy Has Come of Age: The First Durable Complete Response with MetMAb in Metastatic Gastric Cancer

“…and colleagues (6) demonstrated that even a modest increase in MET activation can initiate tumorigenesis and that both the MET mutational spectra and the host stromal tissue background can have profound influence on the type of tumor generated. Hence, personalized combinational MET-targeting therapies would have to take into accounts of any interaction of genetic modifiers and MET oncogenic signaling.…”