Abstract 3859: Ephrin inhibition disrupts stromal-cancer crosstalk and reduces metastasis in pancreatic cancer

Abstract Pancreatic Ductal Adenocarcinoma (PDAC) is the 10th most common cancer in the UK but has devastating mortality rates world-wide. Reasons underpinning this include delays in diagnosis and treatment resistance, where the desmoplastic nature of the disease hampers treatment efficacy. One of the most influential cell types within the PDAC stroma is the cancer associated fibroblast (CAF). CAFs are known to have both pro- and anti-tumoral roles, making them an attractive cell type to target for re-programming. To investigate CAF-cancer cell crosstalk we developed a 3D in vitro model of CAF-led invasion using heterocellular spheroids of cancer cells and CAFs. RNA sequencing of chimeric mouse/human versions of these spheres identified complementary expression of ephrin family receptors (Eph-B2) and ligands (EFNB2) between cancer and CAFs respectively, implicating their involvement in invasion. Part of the receptor tyrosine kinase superfamily, the ephrin family are unique in that both the ligand and receptor can signal, with implications of this having been well described in vasculogenesis and axon guidance. Utilising CAFs expressing either EFNB2 knockout or a gain-of-function mutation in EFNB2, we have found that both forward and reverse signalling is required for invasion, suggesting that disruption of both elements could be beneficial therapeutically. Using first-in-class inhibitors of this pathway, we observed a significant decrease in PDAC invasion in our 3D spheroid invasion model. Extending this in vivo, we have utilised a KPC-derived PDAC orthotopic mouse model that recapitulates human biology through the formation of both primary and metastatic disease. We found that tumour growth and size were not affected by ephrin blockade. However, eph-ephrin signalling inhibition did cause a significant decrease in metastatic tumour presence across multiple organ sites. This highlights a potential for this treatment to halt disease progression and reverse disease severity. We hope to extend these results further to test the potential clinical applications of this compound as a treatment option for both early and late-stage PDAC patients. Citation Format: Cerian L. Bolton, Rhianna O'Sullivan, Shinelle Menezes, Angus J. Cameron, Guillem Marin, John F. Marshall, Ed P. Carter, Mark Henkemeyer, Richard P. Grose. Ephrin inhibition disrupts stromal-cancer crosstalk and reduces metastasis in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3859.