Modular micro-physiological human tumor/tissue models based on decellularized tissue for improved preclinical testing

Johanna Kühnemundt

doi:10.14573/altex.2008141

Abstract

High attrition rates associated with drug testing in 2D cell culture and animal models stress the need for improved modeling of human tumor tissues. In previous studies, our 3D models on a decellularized tissue matrix have shown better predictivity and higher chemoresistance. A single porcine intestine yields material for 150 3D models of breast, lung, colorectal cancer (CRC) or leukemia. The uniquely preserved structure of the basement membrane enables physiological anchorage of endothelial cells and epithelial-derived carcinoma cells. The matrix provides different niches for cell growth: on top as monolayer, in crypts as aggregates, and within deeper layers. Dynamic culture in bioreactors enhances cell growth. Comparing gene expression between 2D and 3D cultures, we observed changes related to proliferation, apoptosis and stemness. For drug target predictions, we utilize tumor-specific sequencing data in our in silico model, finding an additive effect of metformin and gefitinib treatment for lung cancer in silico, validated in vitro. To analyze mode-of-action, immune therapies such as trispecific T-cell engagers in leukemia or toxicity on non-cancer cells, the model can be modularly enriched with human endothelial cells (hECs), immune cells and fibroblasts. Upon addition of hECs, transmigration of immune cells through the endothelial barrier can be investigated. In an allogenic CRC model, we observe a lower basic apoptosis rate after applying PBMCs in 3D compared to 2D, which offers new options to mirror antigen-specific immunotherapies in vitro. In conclusion, we present modular human 3D tumor models with tissue-like features for preclinical testing to reduce animal experiments.

Highlights

1.1 Preclinical test systems in oncology Preclinical models in oncology still rely mostly on two-dimensional (2D) culture and on animal experiments
3.1 Generation of micro-physiological human tumor models on a porcine tissue matrix In order to generate human tumor models representing the in vivo situation more closely than 2D cell cultures or simple spheroids, we used pieces of the porcine intestinal jejunum deriving from the BioVaSc-TERM®
We report here a modular 3D tissue culture system to generate improved human tumor models with an in vivo-like microphysiology

Summary

Introduction

1.1 Preclinical test systems in oncology Preclinical models in oncology still rely mostly on two-dimensional (2D) culture and on animal experiments. 3.5 Differences in gene expression upon targeted therapy under 2D conditions and in 3D tissue models In previous studies, we have shown an improved correlation of drug responses with clinical observations in 3D lung can-

Results

Conclusion