Abstract 1567: Increased extracellular matrix stiffness induces hypersecretion of chemoresistance-promoting cancer associated fibroblast-derived exosomes in pancreatic cancer

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal types of cancer with few effective treatments. Despite recent advances in in other cancers, the five-year survival rate of PDAC is still only 10%, with most patients succumbing to their disease within the first year. One of the main factors responsible for this poor outcome is the development of chemoresistance in nearly all clinical cases. While the intrinsic factors that facilitate chemoresistance in the tumor cells have been studied extensively, fewer studies have elucidated how the complex and unique microenvironment surrounding the tumor affects therapeutic responses. The abundant stromal cells and the stiff desmoplastic microenvironment constitute more than 90% of the primary tumor bulk. However, there is a lack of high-throughput, easily tunable models to recapitulate this complex microenvironment, in order to identify a critical cell-extrinsic factors that could drive acquired chemoresistance in PDAC cells. To address this issue, we have developed a Matrigel-based, orthogonally tunable 3-dimensional (3D) culture system to co-culture mouse derived PDAC organoids and host-matching cancer-associated fibroblasts (CAFs). Using this system, we found that matrix-activated CAFs readily remodel the desmoplastic matrix through lysol-oxidase dependent crosslinking. Moreover, our novel system demonstrates how collagen-I and matrix stiffness affect chemoresistance via the hypersecretion CAF-derived exosomes. Interestingly, our data show that it is CAF-derived exosomes, not the organoid-derived exosomes, that are most important in regulation of proliferation and chemoresistance. Lastly, we identified key cell surface integrins for collagen-I as therapeutic targets to prevent desmoplastic matrix-mediated chemo-resistance in PDAC. Our study provides insights into how matrix composition and stiffness affect therapeutic outcome in PDAC. Moving forward, therapies aimed at interrupting how PDAC cells and stomal cells sense the matrix microenvironment could be utilized to eventually overcome matrix-mediated chemoresistance in PDAC. Citation Format: Weikun Xiao, Chae-Young Eun, Xinyu Zhang, Charlene DeKalb, Mahsa Pahlavan, Bayan Mahgoub, Hanaa Knaneh, Alireza Sohrabi, Stephanie K. Seidlits, Reginald Hill. Increased extracellular matrix stiffness induces hypersecretion of chemoresistance-promoting cancer associated fibroblast-derived exosomes in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1567.