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

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Johanna Kühnemundt
Heidi Leifeld
Florian Scherg
Matthias Schmitt
Lena Nelke
Tina Schmitt
Florentin Baur
Claudia Göttlich
Maximilian Fuchs
Meik Kunz
Matthias Peindl
Caroline Brähler
Corinna Kronenthaler
Jörg Wischhusen
Martina Prelog
Heike Walles
Thomas Dandekar
Gudrun Dandekar
Sarah L. Nietzer

Abstract

High attrition-rates entailed by 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, as well as 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.

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How to Cite
Kühnemundt, J., Leifeld, H., Scherg, F., Schmitt, M., Nelke, L., Schmitt, T., Baur, F., Göttlich, C., Fuchs, M., Kunz, M., Peindl, M., Brähler, C., Kronenthaler, C., Wischhusen, J., Prelog, M., Walles, H., Dandekar, T., Dandekar, G. and Nietzer, S. L. (2020) “Modular micro-physiological human tumor/tissue models based on decellularized tissue for improved preclinical testing”, ALTEX - Alternatives to animal experimentation. doi: 10.14573/altex.2008141.
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