Abstract 6764: Vascularized tumor-on-chip model for evaluating chemotherapeutic-mediated damage to adjacent healthy tissue

Abstract

Abstract Introduction: Systemic chemotherapy is an effective anticancer treatment for all stages of breast cancer, with intravenous (IV) infusion being the principal method of administration. In addition to targeting cancer, systemic chemotherapy can impact the viability and function of surrounding normal tissues and vasculature. Early-discovery research tools comparing novel and existing systemic treatment strategies are urgently needed to support predictive efficacy and toxicity efforts. Microfluidic systems have the potential to fill this need while simultaneously reducing animal use. The overall goal of the study is to use an advanced microfluidic tumor-on-chip system to simultaneously evaluate the therapeutic and toxic effects of IV chemotherapy on normal and cancerous tissues. Materials and Methods: Synthetic Tumor Networks, which are comprised of primary and secondary tissue sites separated by an interconnected vasculature, were developed using in vivo images and fabricated using soft lithography. Primary vascular endothelial cells were used to establish microvasculature. A normal breast cell line (MCF 10A), or a GFP-labeled metastatic human breast cancer cell line (MDA-MB-231/GFP), were cultured in the tissue sites in a three-dimensional (3D) environment using a human-derived hydrogel. The vascular networks were perfused with endothelial cell media under physiological fluid flow conditions to establish the model. An EZH2 methyltransferase inhibitor (EZH2 inhibitor III) was delivered by IV infusion to the model tissues. Real-time monitoring of cellular growth, tumor invasion and extravasation, and cellular viability were performed using fluorescence microscopy over a two-week period. Results and Discussion: Metastatic MDA-MB-231/GFP breast cancer cells proliferated rapidly in the primary tumor site. Tumor intravasation into the vascular channels was observed in models that received no anticancer treatment, as well as extravasation into the secondary tissue site and invasion of the healthy breast tissue. Differences in tumor viability and migratory behavior were observed between untreated models or models receiving IV infusions of the EZH2 inhibitor through the vascular networks. Vascular barrier integrity and normal breast tissue viability were monitored at early (24-72 hr) and late (7-14 days) timepoints after anticancer treatment to measure short- and long-term adverse drug impacts. These results provide a unique perspective on the in vivo realism of an in vitro system for monitoring both therapeutic and toxic effects of systemic chemotherapies. Conclusions: We have developed a 3D vascularized tumor-on-chip model for monitoring the impacts of systemic chemotherapeutic agents on tumor and healthy tissues. This model can be used to investigate therapeutic and toxic effects on multiple tissue types simultaneously using real-time imaging techniques. Citation Format: Deborah Ramsey, Jenna Rosano, Cristabel Gordon, Gwen Fewell. Vascularized tumor-on-chip model for evaluating chemotherapeutic-mediated damage to adjacent healthy tissue [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6764.