Abstract A22: In situ image-based monitoring of extracellular matrix mechanics in 3D pancreatic tumor-stroma co-culture models to inform therapeutic development

Abstract

Abstract A number of compelling studies have shown that the mechanical landscape of the tumor microenvironment contributes significantly to regulation of growth behavior, phenotype, and therapeutic response. These findings could be particularly relevant to pancreatic tumors, which are associated with a profound desmolastic reaction. The exceptional abundance of rigid, fibrotic stroma encasing these lethal malignancies has been implicated in obstructing drug delivery and playing multiple tumor-promoting roles. In this context, we use in vitro 3D tumor models with customized stromal composition, combined with in situ quantitative measurements of extracellular matrix (ECM) rigidity via optical microrheology, as a platform for evaluation of therapeutics targeting biomechanical interactions with the microenvironment. Using ECM formulations of calibrated rheological properties (rigidity) in conjunction with optical measurements that provide readouts of dynamic changes provides a window into both sides of a mechanoregulatory dialogue, in which ECM rigidity influences tumor growth and, in turn, cancer cells and stromal fibroblasts remodel their mechanical environment. Here we examine differential therapeutic response to selected chemotherapy agents and photodynamic therapy (PDT) in culture conditions that lead to fibrosis (increasing mechanical strength) as well invasive behavior (local breakdown of ECM). The methodology used here could be more broadly applied to directly quantify impact of stromal depletion therapies and altered ECM remodeling concomitant with therapy. Citation Format: Dustin P. Jones, William Hanna, Gwendolyn M. Cramer, Hamid El-Hamidi, Jonathan P. Celli. In situ image-based monitoring of extracellular matrix mechanics in 3D pancreatic tumor-stroma co-culture models to inform therapeutic development. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr A22.