Abstract 285: Organ chip culture of vascularized triple negative breast cancer explant tissues with validated pathological and clinically-targetable properties of tumor vasculature
Authors: Conrad Kevin M. , Byrne Charles E. , Burow Matthew R. , Mondrinos Mark 
Published: June 2022

Abstract
Triple negative breast cancer (TNBC) is an aggressive subtype characterized by a lack of the classic targetable receptors. Targeting the TNBC microenvironment via the biophysical properties of the tumor vasculature is a promising approach. The objective of this study was to engineer a microphysiological model of vascularized TNBC with validated pathological properties of tumor vasculature for in vitro modeling of selective drug delivery via the enhanced permeability and retention effect. We engineered a method for standardized production of milliscale tissues housed in fluidic culture devices that are accessible only via a fully anastomosed and perfusable internal vasculature comprised of endothelial cells and organ specific fibroblasts. We first established a baseline of vascular morphometry, endothelial barrier function, inflammatory activation, and perivascular extracellular matrix (ECM) composition in vascularized tissues devoid of cancer cells. In parallel, we developed a novel approach for processing patient-derived TNBC tissues into injectable explants of disaggregated tumor imbibed in ECM hydrogel in less than one hour. These explant tissues cultured in our devices consistently maintain high viability and a Ki67 index around 70%, on par with the Ki67 indexes of source TNBC tumors. We hypothesized that TNBC derivatives would induce the formation of a pathological vasculature in our model. The TNBC derivatives were mixed with exogenous fibroblasts and endothelial cells at optimized ratios and the same workflow described above was used to form vascularized TNBC explant tissues. TNBC-associated vasculature exhibited a significantly altered vascular morphometry relative to cancer-free control tissues across multiple quantitative metrics including vessel length, vessel diameter, and network branch points. These morphological changes were consistent with known dysmorphic features of tumor vasculature. Twofold or greater increases in endothelial ICAM-1 expression in TNBC-associated vasculature was measured by multiple methods of analysis. Increased inflammatory adhesion molecule expression was accompanied by disorganized VE-cadherin junctions and disrupted patterns of perivascular cell coverage that suggested TNBC-associated vasculature should be significantly more permeable. FITC-dextran perfusion studies revealed widespread macromolecular leakage from TNBC-associated vasculature into the TNBC explant tissue interstitium by 5 minutes, whereas no leakage was observed from control vasculature for the duration of perfusion up to one hour. Ongoing work to be presented is focused on validating our model as a platform for studying drug delivery via the enhanced permeability and retention effect using Abraxane nanoparticles.
Citation Format: Kevin M. Conrad, Charles E. Byrne, Matthew R. Burow, Mark Mondrinos. Organ chip culture of vascularized triple negative breast cancer explant tissues with validated pathological and clinically-targetable properties of tumor vasculature [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 285.