Abstract LB454: Targeting the epithelial-stromal cell crosstalk in metastatic pancreatic cancer

Abstract Pancreatic Ductal Adenocarcinoma (PDA) is a devastating disease with a 5-year survival of 13%. However, if detected at an earlier stage, PDA has a 5-year survival of more than 30%. Accordingly, the dismal prognosis can be ascribed to late diagnosis after the disease has metastasized, most frequently to the liver. However, work to develop treatments have been largely designed for primary PDA cells residing in hypoxic & nutrient deficient tumor microenvironment (TME) of the pancreas. It is likely that these treatments will not be equally effective against metastasized PDA cells in a vascularized and nutrient rich organ such as the liver. This calls for treatments specific to the metastatic niche. The primary PDA TME has been extensively studied. We and others have shown that immune and stromal populations engage in extensive crosstalk promoting proliferation of cancer cells and resistance to treatments such as immunotherapy and chemotherapy. However, how these crosstalk mechanisms promote the establishment and growth in the PDA metastatic niche remain less understood. Here, we show a unique crosstalk between fibroblasts and cancer cells, specifically in the metastatic niche, that can be targeted for therapeutic benefit. In this study, we compare the TME of primary PDA with the liver metastatic niche. Syngeneic KPC (Kras+/LSL-G12D;Trp53+/LSL-R172H; Pdx1-Cre) cells were injected orthotopically in the pancreas to establish primary tumors or in the liver through hemi spleen surgeries. Single cell RNA sequencing revealed unique population of fibroblasts in the liver metastatic niche. Using CellChat, we identified upregulation of the HGF-MET signaling axis specifically in the liver. We also verified our murine data in human CAFs grown out from patient tissues. We next knocked out Met via CRISPR and our data show significant increase in survival in mice. Next, we used the MET inhibitor- XL-184 (Cabozantinib) as a treatment option and our data show significant reduction in metastatic tumors and increased survival in vivo. Overall, we have found a unique epithelial and stromal crosstalk in the liver that can be targeted to treat metastatic PDA. Citation Format: Rima Singh, Natalie Yousefian, Nina Steele, Christopher Halbrook. Targeting the epithelial-stromal cell crosstalk in metastatic pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB454.