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2013|14 Annual Report Fraunhofer IGB

89 Claudia Göttlich M.Sc. Phone +49 931 31-88521 claudia.goettlich@uni-wuerzburg.de Prof. Dr. Heike Walles Phone +49 931 31-88828 heike.walles@igb.fraunhofer.de References [1] Ferlay, J. et al. (2010) Int J Cancer 127: 2893 – ​2917 [2] Mok, T. S. et al. (2009) N Engl J Med 361: 947 – ​957 [3] Mertsching, H. et al. (2005) Biomaterials 33: 6610 – ​6617 [4] Bronte, G. et al. (2010) Cancer Treat Rev 36 Suppl 3: 21 – ​29 [5] Schlatter, R. et al. (2012) Brief Bioinform 13: 365 – ​376 [6] Stratmann, A. T. et al. (2013) in press; http://dx.doi. org/10.1016/j.molonc.2013.11.009 complexes of the EGFR signaling pathways. First, a map (to- pology) of the EGFR signaling network with connections to other important tumor development pathways, such as TGF-β (transforming growth factor), was established. The pathway of the signal cascades over various nodes where signals cross were programmed to specific cell responses, such as division or death. There already exists a sound groundwork on other cell types using these semi-quantitative Boolean models [5]. The in-silico model can thus provide predictions of the chang- ing division, death and invasion of tumor cells when certain nodes of the network are stimulated or blocked by drugs or other factors. As in the clinic, two different lung tumor types were tested in the network – with and without the EGFR-mutation – in response to changes of the blocking the EGFR on cells (simula- tion: gefitinib therapy). The optimized in-silico model predic- tions were consistent with the in-vitro model as well as with observations from the clinic. The data obtained from the in-vitro experiments were used to further refine the in-silico model, adding new nodes in the network topology. Thus, we want to find other therapeutic targets and validate their clini- cal relevance in the in-vitro lung tumor model. Outlook With the combined in-vitro / in-silico lung tumor model, we were able to simulate a clinically successful therapy [6]. This shows the high potential of our models to produce clinically relevant results. The goal is now to find other therapeutic ap- proaches and to test the models in order to establish effective treatment methods. We are currently investigating KRAS- mutated cell lines (A549, H441) to identify biomarkers for personalized medicine. In addition, we want to create models with primary cells from patient samples in static and dynamic cultures on the SISmuc with bioreactors in order to better re- flect the in-vivo situation. 1 E-cadherin/β-catenin staining of lung carcinoma. 2 Reduced rate of division in 3D in comparison to the conventional 2D culture. 3 Activation of EGFR by HCC827 cells cultured on the SISmuc. 4 HCC827 cells form a layer of epithelium on the SISmuc (H & E staining). Development of other 3D tumor in-vitro models Other than the lung tumor model, we are working on the de- velopment of further 3D tumor models. These include models for colorectal cancer, breast cancer, leukemia and malignant peripheral nerve sheath tumors (MPNST). Contacts 43

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