Abstract B060: ERMCS induction drives ADM in ex vivo models

Abstract Acinar cells, which synthesize digestive enzymes, undergo acinar-to-ductal metaplasia (ADM) upon injury, a process implicated in early pancreatic tumorigenesis. Previous studies suggest that ADM involves metabolic rewiring, and that mitochondrial fission is critical for established tumor cells survival. Emerging evidence suggests that interactions between mitochondria and the endoplasmic reticulum (ER) at ER-mitochondria contact sites (ERMCS) may regulate these early events. However, the interplay between metabolism, organelle dynamics, and ADM remains poorly understood. We hypothesize that disruption of ERMCS will impair mitochondrial fission and hinder ADM progression toward malignancy. Using ex vivo organoid models derived from acinar cells of our newly developed split-GFP based contact site sensor (SPLICS) reporter mouse – a cutting-edge tool engineered to express a whole-body, tamoxifen-inducible SPLICS reporter which allows real-time quantification of ERMCS – we investigated the effects of Fedratinib, an ERMCS inducer recently characterized by our research group. Fedratinib demonstrated a potent ability to activate ERMCS and ADM in acinar cells derived from SPLICS mice ex vivo. Treatment with Fedratinib resulted in the formation of ductal-like structures in quantities comparable to those induced by our positive control, which involves KRAS-MAPK pathway activation through TGF-α signaling, although these structures were marginally smaller in size than those formed with TGF-α alone. Importantly, detection of GFP signal further confirmed the enhanced proximity of ER and mitochondria, supporting Fedratinib’s efficacy as an ERMCS activator. Our recent studies have demonstrated that Fedratinib exerts its effects via inhibition of BRD4, a key regulator of gene transcription during cell proliferation and differentiation. Furthermore, the inhibition of BRD4 has been previously linked to accelerated ADM and impaired tissue regeneration post-injury. Our findings establish Fedratinib as a potent activator of ERMCS and ADM in ex vivo pancreatic models. This supports a novel link between ER-mitochondrial dynamics and cell fate transitions during pancreatic injury. These results provide a platform for further investigation of mitochondrial network alterations and the potential for targeting ERMCS in prevention and early detection of pancreatic cancer. Citation Format: Mariana Tannús Ruckert, Megan D. Radyk, Brandon Chen, Yatrik Shah, Costas A. Lyssiotis. ERMCS induction drives ADM in ex vivo models [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr B060.