Comparative Analysis of Primary and Liver Fibroblasts Reveals MET as a Potent Target in Pancreatic Cancer Metastasis

BACKGROUND AND AIMS: The tumor microenvironment drives many malignant features of pancreatic ductal adenocarcinoma (PDAC). The fibroblasts within pancreatic tumors promote tissue remodeling, immune suppression, and resistance to therapy. However, the interactions between stromal populations and pancreatic cancer cells are less understood in the liver, the most frequent site of PDAC metastasis. METHODS: To address this, we employ single cell transcriptomics to compare primary pancreatic vs. liver PDAC lesions. Using a ligand-receptor interaction tool, we assess upregulated pathways in liver PDAC. RESULTS: Here, we identify the expression of hepatocyte growth factor (HGF) in fibroblasts and its receptor MET in cancer cells are both markedly increased in the PDAC liver niche. Using functional assays, we validate that mitogenic MET signaling is activated in PDAC cells by liver-derived fibroblasts. Importantly, the inhibition of MET signaling leads to reduced tumor growth in immune competent mouse models. CONCLUSIONS: Collectively, our data demonstrates that liver stromal-epithelial crosstalk networks engage in signaling pathways distinct from primary pancreatic tumors, highlighting opportunities to develop new treatments for metastatic disease.