Johanna Kühnemundt
Department Tissue Engineering and Regenerative Medicine, University Hospital Würzburg, Würzburg, Germany
Heidi Leifeld
Department Tissue Engineering and Regenerative Medicine, University Hospital Würzburg, Würzburg, Germany
Florian Scherg
Department Tissue Engineering and Regenerative Medicine, University Hospital Würzburg, Würzburg, Germany
Matthias Schmitt
Department Tissue Engineering and Regenerative Medicine, University Hospital Würzburg, Würzburg, Germany
Lena C. Nelke
Department Tissue Engineering and Regenerative Medicine, University Hospital Würzburg, Würzburg, Germany
Tina Schmitt
Department Tissue Engineering and Regenerative Medicine, University Hospital Würzburg, Würzburg, Germany
Florentin Baur
Department Tissue Engineering and Regenerative Medicine, University Hospital Würzburg, Würzburg, Germany; Translational Center Regenerative Therapies, Fraunhofer Institute for Silicate Research ISC, Würzburg, Germany
Claudia Göttlich
Department Tissue Engineering and Regenerative Medicine, University Hospital Würzburg, Würzburg, Germany; Translational Center Regenerative Therapies, Fraunhofer Institute for Silicate Research ISC, Würzburg, Germany
Maximilian Fuchs
Bioinformatics, Biocenter, University of Würzburg, Würzburg, Germany
Meik Kunz
Bioinformatics, Biocenter, University of Würzburg, Würzburg, Germany; Chair of Medical Informatics, Friedrich-Alexander University (FAU) of Erlangen-Nürnberg, Erlangen, Germany
Matthias Peindl
Department Tissue Engineering and Regenerative Medicine, University Hospital Würzburg, Würzburg, Germany
Caroline Brähler
Department Tissue Engineering and Regenerative Medicine, University Hospital Würzburg, Würzburg, Germany
Corinna Kronenthaler
Department Tissue Engineering and Regenerative Medicine, University Hospital Würzburg, Würzburg, Germany
Jörg Wischhusen
University Hospital Würzburg, Department for Obstetrics & Gynecology, Section for Experimental Tumor Immunology, University of Würzburg, Würzburg, Germany
Martina Prelog
Children’s University Hospital, Pediatric Rheumatology/Special Immunology, University of Würzburg, Würzburg, Germany
Heike Walles
Department Tissue Engineering and Regenerative Medicine, University Hospital Würzburg, Würzburg, Germany; Translational Center Regenerative Therapies, Fraunhofer Institute for Silicate Research ISC, Würzburg, Germany; FVST, Core Facility Tissue Engineering, Otto-von Guericke University, Magdeburg, Germany
Thomas Dandekar
Bioinformatics, Biocenter, University of Würzburg, Würzburg, Germany
Gudrun Dandekar
Department Tissue Engineering and Regenerative Medicine, University Hospital Würzburg, Würzburg, Germany; Translational Center Regenerative Therapies, Fraunhofer Institute for Silicate Research ISC, Würzburg, Germany
Sarah L. Nietzer
Department Tissue Engineering and Regenerative Medicine, University Hospital Würzburg, Würzburg, Germany; Translational Center Regenerative Therapies, Fraunhofer Institute for Silicate Research ISC, Würzburg, Germany
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.
