Cellular and molecular gastroenterology and hepatology · 2026
Comparative Analysis of Primary and Liver Fibroblasts Reveals MET as a Potent Target in Pancreatic Cancer Metastasis.
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Singh Rima, Yousefian Natalie, Allen Walker M, Silva Austin D, Anaraki Cecily, Michels Alica K, Calderon Sabrina, Loveless Ian M, Rastelli Daniella, George Ashley, Aldakkak Mohammed, McDonald Oliver G, Lytle Nikki K, Morton Jennifer P, Ayabe Reed I, Imagawa David, Jutric Zeljka, Martinez Thomas F, Steele Nina G, Halbrook Christopher J
Аннотация
BACKGROUND & AIMS: The tumor microenvironment drives many malignant features of pancreatic ductal adenocarcinoma. 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 pancreatic ductal adenocarcinoma metastasis.
METHODS: To address this, we employed single-cell transcriptomics to compare primary pancreatic vs liver pancreatic ductal adenocarcinoma lesions. Using a ligand-receptor interaction tool, we assessed upregulated pathways in liver pancreatic ductal adenocarcinoma.
RESULTS: Here, we identified that the expression of hepatocyte growth factor in fibroblasts and its receptor MET in cancer cells are both markedly increased in the pancreatic ductal adenocarcinoma liver niche. Using functional assays, we validated that mitogenic MET signaling is activated in pancreatic ductal adenocarcinoma 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.
METHODS: To address this, we employed single-cell transcriptomics to compare primary pancreatic vs liver pancreatic ductal adenocarcinoma lesions. Using a ligand-receptor interaction tool, we assessed upregulated pathways in liver pancreatic ductal adenocarcinoma.
RESULTS: Here, we identified that the expression of hepatocyte growth factor in fibroblasts and its receptor MET in cancer cells are both markedly increased in the pancreatic ductal adenocarcinoma liver niche. Using functional assays, we validated that mitogenic MET signaling is activated in pancreatic ductal adenocarcinoma 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.