Establishment of a human 3D lung cancer model based on a biological tissue matrix combined with a Boolean in silico model. Issue 2 (18th December 2013)

• Record Type: Journal Article
• Authors: Stratmann, Anna T.; Fecher, David; Wangorsch, Gaby; Göttlich, Claudia; Walles, Thorsten; Walles, Heike; Dandekar, Thomas; Dandekar, Gudrun; Nietzer, Sarah L.
• Is Part Of: Molecular oncology. Volume 8:Issue 2(2014:Mar.)
• Page Start: 351
• Page End: 365
• Publication Date: 2013-12-18
• Subjects: 3D tumor model -- Boolean model -- EMT -- Invasion -- Personalized medicine -- Targeted therapy; Cancer -- Molecular aspects -- Periodicals; 616.994005
• DOI: 10.1016/j.molonc.2013.11.009
• Languages: English
• ISSNs: 1574-7891

Abstract

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. Highlights: Combination of a human 3D lung tumor tissue model with a Boolean in silico Model. Establishment of in silico signaling network topology for personalized medicine. Significant decrease of tumor proliferation and induction of apoptosis upon in vitro treatment with tyrosine kinase inhibitors. Decreased proliferation of tumor cells in the 3D model compared to 2D conditions. Induction of invasion with EMT by TGFβ stimulation.