Abstract B061: Development of a pancreatic ductal adenocarcinoma 3D tumor model for high-throughput drug screening

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a persistent malignancy that is difficult to diagnose in its early stage and is one of the leading cancer-related deaths worldwide. Currently, limited therapeutic options are available for PDAC, resulting in an extremely low 5-year survival rate. To speed up the discovery of novel therapeutics, a reliable 3D model that highly simulates the PDAC tumor microenvironment is needed for large-scale drug screening. In this study, we propose a novel 3D model for restoring the PDAC tumor microenvironment by targeting cancer-associated fibroblasts (CAFs), which serve as the key component of the PDAC, providing its heterogeneity and contributing to reciprocal signaling and drug resistance. Our previous studies have demonstrated that Adipose-derived mesenchymal stem cells can differentiate into varying subtypes CAFs when co-cultured with PDAC cells both in vitro and in vivo. Following this strategy, we utilize the fibroblast-populated collagen lattice (FPCL) modeling approach, which relies on the contractility of fibroblasts in a collagen gel matrix, to provide the mechanical stress and hypoxic conditions for the 3D tumor models. Human Adipose-derived mesenchymal stem cells as CAF precursors and PDAC cell lines were mixed with collagen solution to make the collagen discs, resulting in the formation of 3D PDAC tumor models within a week. The morphological analyses, along with global transcriptome and metabolomic analyses, were performed to confirm the clinical-like mature ductal glands of PDAC cells and CAFs-like spindle-shaped of mesenchymal stem cells in the interior of PDAC-FPCL (PDAC-F). Moreover, the PDAC-F has shown a high tumorigenic potential in vivo animal model. Additionally, PDAC-F was shown to allow combination therapies screening of anticancer and antifibrotic drugs in the drug screening test, demonstrating that the combination therapeutics have better efficacy. In conclusion, our PDAC-F is built with distinct features of PDAC, reproducing the heterogeneous and high stiffness with a clinical-like PDAC morphology. In addition, the short modeling time and the high reproducibility of this PDAC-F open the possibilities for large-scale drug screening, which is expected to accelerate new drug development and provide effective treatment for pancreatic cancer patients. Citation Format: Xiaoyu Song, Yuma Nihashi, Yasuyuki S. Kida. Development of a pancreatic ductal adenocarcinoma 3D tumor model for high-throughput drug screening [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B061.