Investigating a Novel Interaction of c-MET and BACH1 in Head and Neck Squamous Cell Carcinoma Metastasis

Metastasis is estimated to be responsible for 90% of cancer deaths, and fewer than 10% of patients with metastatic head and neck squamous cell carcinoma (HNSCC) survive beyond 5 years. HNSCC is responsible for upwards of 270,000 global deaths annually, with up to 30% more cases projected annually by 2030. The proto-oncogene MET encodes for the tyrosine kinase receptor c-MET, which is overexpressed in over 80% of human papilloma virus (HPV)-negative HNSCC cases and particularly enriched in metastatic lymph nodes. c-MET is activated by its ligand, hepatocellular growth factor (HGF), and is known to promote cancer cell migration, proliferation, and metastasis through a variety of downstream effectors. Thus far, unfortunately, inhibition of c-MET has shown low efficacy as a single-agent therapy in clinical trials, which indicates a need for further understanding of the mechanisms underlying c-MET-mediated metastasis in HNSCC. We show here that human HNSCC cells upregulate expression of the transcription factor BACH1 through c-MET activation upon HGF treatment. In accordance with previous reports, HGF activation increased expression of epithelial-mesenchymal transition (EMT) markers. Similarly, BACH1 suppression reduced expression of these EMT markers. By pharmacological inhibition of c-MET by FDA-approved capmatinib in combination with hemin treatment to reduce BACH1 expression, migration was reduced compared to either treatment alone in scratch-wound migration assays. Collectively, these data indicate that BACH1 and c-MET are both necessary for the regulation of EMT and migration in HNSCC. Our data suggest the potential for combination therapy targeting both c-MET and BACH1 to reduce HNSCC metastasis. HNSCC cell lines FaDu, Detroit562, and Cal27 were established as paired shControl and shBACH1 cells lines. Each cell line was then cultured and treated for 0, 3, or 6 hours with HGF and RNA collected for sequencing.