Mechanisms of MET-dependent tumour initiation and progression

MET is a receptor tyrosine kinase that, when dysregulated, contributes to oncogenic progression in a wide range of human cancers. When activated, MET coordinates a program of invasive growth and migration that largely overlaps with the process of epithelial-mesenchymal transition (EMT). The induction of an EMT program can generate cells with increased tumourigenicity and properties associated with stem cells. Cells enriched with tumour-initiating capacity are commonly termed tumour-initiating cells (TICs) and have been found to be resistant to conventional therapies and thus can contribute to recurrence. Indeed, TICs possess a gene signature that converges with cells that have undergone an EMT. MET is implicated in TIC regulation in a number of cancers, however the mechanisms by which it promotes the propagation of TICs has yet to be fully elucidated. Breast cancer is a heterogeneous disease with multiple distinct subtypes that differ both in gene expression and prognosis. Triple negative breast cancer (TNBC) is an aggressive subtype that is negative for expression of estrogen receptor, progesterone receptor, and HER2 amplification, and therefore lacks targeted therapies and has poor prognosis. Elevated levels of MET are observed in 15-20% of all breast cancers and is associated with TNBC as well as poor survival. Using a MMTV-Metmt;Trp53fl/+;Cre murine model of the claudin-low subtype of TNBC, which features highly mesenchymal tumours with amplified and constitutively active Met protein, we show that a Met-dependent EMT program is required for an enhanced tumour-initiating capacity. We uncover a mechanism by which signaling through Met and fibroblast growth factor receptor 1 (FGFR1) can both independently regulate tumourigenic potential, and combinatorial targeting of both receptors is needed to abrogate TICs in both in vitro and in vivo studies. We find co-expression of MET and FGFR1 in human TNBC cell lines and in patient-derived xenografts of TNBC, and that dual inhibition of both receptors likewise depletes TIC populations. Importantly, human TNBCs with highly mesenchymal characteristics are significantly enriched for expression of HGF and FGFR1 expression, and co-expression predicts poor prognosis among these patients. These findings provide a role for MET in TNBC tumour initiation and maintenance, where it sustains a mesenchymal program that promotes a state of cellular plasticity conducive to tumourigenesis. Co-regulation of TICs by MET and FGFR1 is facilitated by pathways mediated through FGFR substrate 2 (FRS2), a scaffold protein first identified in FGFR signaling. While MET is not conventionally known to signal through FRS2, we find that FRS2 is in fact required for MET-dependent cellular processes such as invasion and survival in a number of MET-amplified cancer cell lines. We further show in breast cancer cell lines that HGF-stimulated activation of non-amplified and wildtype MET promotes FRS2 phosphorylation and maintains ERK1/2 phosphorylation in the absence of FGFR signaling. These findings describe a previously uncharacterized role for FRS2 in MET-driven biology.

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