title: Establishment of a human 3D lung cancer model based on a biological tissue matrix combined with a Boolean in silico model.
abstract: For the development of new treatment strategies against cancer, understanding signaling networks and their changes upon drug response is a promising approach to identify new drug targets and biomarker profiles. Pre-requisites are tumor models with multiple read-out options that accurately reflect the clinical situation. Tissue engineering technologies offer the integration of components of the tumor microenvironment which are known to impair drug response of cancer cells. We established three-dimensional (3D) lung carcinoma models on a decellularized tissue matrix, providing a complex microenvironment for cell growth. For model generation, we used two cell lines with (HCC827) or without (A549) an activating mutation of the epidermal growth factor receptor (EGFR), exhibiting different sensitivities to the EGFR inhibitor gefitinib. EGFR activation in HCC827 was inhibited by gefitinib, resulting in a significant reduction of proliferation (Ki-67 proliferation index) and in the induction of apoptosis (TUNEL staining, M30-ELISA). No significant effect was observed in conventional cell culture. Results from the 3D model correlated with the results of an in silico model that integrates the EGFR signaling network according to clinical data. The application of TGFβ1 induced tumor cell invasion, accompanied by epithelial-mesenchymal transition (EMT) both in vitro and in silico. This was confirmed in the 3D model by acquisition of mesenchymal cell morphology and modified expression of fibronectin, E-cadherin, β-catenin and mucin-1. Quantitative read-outs for proliferation, apoptosis and invasion were established in the complex 3D tumor model. The combined in vitro and in silico model represents a powerful tool for systems analysis.
authors.affiliation: Department of Tissue Engineering and Regenerative Medicine, University Hospital of Wuerzburg, Roentgenring 11, 97070 Wuerzburg, Germany.
authors.forename: Anna T
authors.initials: AT
authors.lastname: Stratmann
authors.affiliation: Department of Tissue Engineering and Regenerative Medicine, University Hospital of Wuerzburg, Roentgenring 11, 97070 Wuerzburg, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Fecher
authors.affiliation: Department of Bioinformatics, University Wuerzburg, Am Hubland/Biozentrum, 97074 Wuerzburg, Germany.
authors.forename: Gaby
authors.initials: G
authors.lastname: Wangorsch
authors.affiliation: Department of Tissue Engineering and Regenerative Medicine, University Hospital of Wuerzburg, Roentgenring 11, 97070 Wuerzburg, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Göttlich
authors.affiliation: Department of Cardiothoracic Surgery, University Hospital of Wuerzburg, Oberduerrbacher Str. 6, 97080 Wuerzburg, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Walles
authors.affiliation: Department of Tissue Engineering and Regenerative Medicine, University Hospital of Wuerzburg, Roentgenring 11, 97070 Wuerzburg, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Walles
authors.affiliation: Department of Bioinformatics, University Wuerzburg, Am Hubland/Biozentrum, 97074 Wuerzburg, Germany. Electronic address: dandekar@biozentrum.uni-wuerzburg.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Dandekar
authors.affiliation: Department of Tissue Engineering and Regenerative Medicine, University Hospital of Wuerzburg, Roentgenring 11, 97070 Wuerzburg, Germany. Electronic address: gudrun.dandekar@uni-wuerzburg.de.
authors.forename: Gudrun
authors.initials: G
authors.lastname: Dandekar
authors.affiliation: Department of Tissue Engineering and Regenerative Medicine, University Hospital of Wuerzburg, Roentgenring 11, 97070 Wuerzburg, Germany.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Nietzer
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008954:Models, Biological; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology; D015398:Signal Transduction; D013552:Swine; D059016:Tumor Microenvironment
chemical_list: D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D011799:Quinazolines; D000077156:Gefitinib
keywords: 3D tumor model; Boolean model; EMT; Invasion; Personalized medicine; Targeted therapy