Abstract 1236: Immune competent 3D pancreatic adenocarcinoma (PDAC)-on-chip model for preclinical drug discovery

Abstract Representing the most common malignancy of the pancreas, pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer type with a five-year survival rate of less than 13%. To date, targeted treatment regiments are not available, leaving only cytotoxic chemotherapy with gemcitabine or FOLFIRINOX as the first-line-treatment for patients who are ineligible for surgical resection. One factor which contributes to the lack of efficient treatment options is the presence of a highly fibrotic and immunosuppressive tumor microenvironment (TME), mainly consisting of cancer associated fibroblasts (CAF) and tumor associated macrophages (TAM). Furthermore, effective treatments require drug candidates to pass the endothelium into the tumor. This barrier is not addressed in most in vitro models traditionally used in drug screening. Thus, novel PDAC models reflecting, the cellular heterogeneity within the TME including a vascular linkage will be essential to find efficacious treatment strategies. Using the Dynamic42 biochip platform, which allows dynamic culturing of cells in three channels each separated by porous membranes, we generated a fit-for-purpose 3D model of human PDAC. The model combines a perfused vasculature with an underlying tumor tissue consisting of tumor spheroids with a CAF hull embedded into an extracellular matrix (ECM). We first used this PDAC-on-chip model as a proof-of-principle to deliver small molecule drug candidates via a vasculature to the 3D spheroids. As one example, we identified vorinostat, a histone deacetylase inhibitor already approved for cutaneous T cell lymphoma, significantly reducing PDAC spheroid viability in a dose dependent manner without impacting the vascular integrity. We further expanded the PDAC-on-chip model by introducing peripheral blood mononuclear cells (PBMC)-derived monocytes. We show that monocytes applied through the vasculature invade through the endothelial barrier and migrate into CAF rich areas, where they differentiate to M2-like macrophages upregulating CD163 and loosing CD86 and HLA-DR expression. We now use this system to study T cell invasion, as well as direct vascularization of PDAC tumors. Citation Format: Alina Deipenbrock, Ben Eric Wilmes, Kyra Moustakas, Irene Esposito, Thomas Sommermann, Martin Raasch, Nicole Teusch. Immune competent 3D pancreatic adenocarcinoma (PDAC)-on-chip model for preclinical drug discovery [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 1236.