Development of a Novel 3D Tumor-tissue Invasion Model for High-throughput, High-content Phenotypic Drug Screening

Abstract

While much progress has been made in the war on cancer, highly invasive cancers such as pancreatic cancer remain difficult to treat and anti-cancer clinical trial success rates remain low. One shortcoming of the drug development process that underlies these problems is the lack of predictive, pathophysiologically relevant preclinical models of invasive tumor phenotypes. While present-day 3D spheroid invasion models more accurately recreate tumor invasion than traditional 2D models, their shortcomings include poor reproducibility and inability to interface with automated, high-throughput systems. To address this gap, a novel 3D tumor-tissue invasion model which supports rapid, reproducible setup and user-definition of tumor and surrounding tissue compartments was developed. High-cell density tumor compartments were created using a custom-designed fabrication system and standardized oligomeric type I collagen to define and modulate ECM physical properties. Pancreatic cancer cell lines used within this model showed expected differential invasive phenotypes. Low-passage, patient-derived pancreatic cancer cells and cancer-associated fibroblasts were used to increase model pathophysiologic relevance, yielding fibroblast-mediated tumor invasion and matrix alignment. Additionally, a proof-of-concept multiplex drug screening assay was applied to highlight this model's ability to interface with automated imaging systems and showcase its potential as a predictive tool for high-throughput, high-content drug screening.