Abstract 2349: Investigating the effect of ECM stiffness on macrophage-derived exosome secretion and PDAC organoid progression

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) has a 5-year survival rate of only 11%. Current treatments that mostly target the cancer cells themselves, have not been able to significantly improve survival rates, meaning there is an urgent need for novel therapies. PDAC is unique among solid tumors because it exhibits extensive desmoplasia that is characterized by an abundance of extracellular matrix (ECM) components. In recent years, an increasing body of work has shown that cancer tissue is stiffer than normal tissue by a factor of 3 or more. This change in ECM stiffness has been shown to play an important role in affecting cell to cell communication as well as cancer progression and chemoresistance. However, how ECM stiffness affects macrophages, an important immune component of the pancreatic tumor microenvironment (TME), and macrophage-derived exosome secretion is still understudied. Preliminary studies have shown that macrophages are highly sensitive to the mechanical environment. How cell-cell information transfer through exosomes may regulate this process in the PDAC tumor microenvironment (TME) needs to be explored. Elucidating these potential changes can provide us with insights on how stiffness affects therapeutic outcome in PDAC. Our previous studies utilizing a biomimetic model that allows us to tune stiffness, showed that increased stiffness resulted in significantly higher exosome secretion from fibroblasts. Based on this finding, we hypothesize that increasing stiffness will result in hypersecretion of macrophage-derived exosomes that increases the chemoresistance of PDAC. 2D culture of macrophages on varying stiffness plates was used to study these changes in vitro. We then examined how changes in ECM stiffness affected the function and polarization of tumor associated macrophages, as well as elucidating how exosome hypersecretion and uptake, regulate these “stiffness enhanced” macrophages’ ability to affect PDAC progression. Understanding how macrophage-derived exosome signaling changes due to ECM stiffness may provide us with insights needed to develop novel therapies. Citation Format: Bayan Mahgoub, Weikun Xiao, Reginald Hill. Investigating the effect of ECM stiffness on macrophage-derived exosome secretion and PDAC organoid progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2349.