Head: Özgür Sahin
Members: Stefan Uhlmann, Aoife Ward, Aleksandra Balwierz, Sara Burmester, Moritz Küblbeck, Marek Baumann, Aysenur Torun
Former members: Anja Schwäger, Özlem Sener Sahin

Receptor Tyrosine Kinases (RTKs) play essential roles in the transduction of external stimuli and enable cells to respond to their environment properly. Many alterations of these kinases through mutations, gene amplifications or protein overexpression strongly affect, and mostly enhance, the development of cancer. For this reason, they have been in the center of targeted cancer therapy both in adjuvant and metastasis settings. In order to elucidate the contribution of RTKs/their downstream mediators as well as other factors (e.g. miRNAs) in cancer progression and metastasis, our group focuses on:

1. Mechanisms of drug resistance against targeted therapies in breast cancer
In cancer, ErbB receptor family members, especially EGFR and ErbB2, are frequently dysregulated through gene amplification, overexpression, deletions, or mutations. Trastuzumab/Herceptin is administered for the treatment of patients with ErbB2-overexpressing metastatic breast cancer. However, the response rate to Trastuzumab in patients is rather low. Recently, we have identified several alternative targets by combining computer simulations and experimental validations in a Trastuzumab resistant breast cell system using a systems biology approach. Currently, we are studying the involvement of other genetic and epigenetic factors in de novo or acquired drug resistance to several ErbB-receptor targeting molecules (e.g. Trastuzumab, gefitinib, etc).

2. Regulators of tumor cell migration/invasion in breast cancer
Most critical for late-stage cancer is the metastasis process, which is responsible for up to 90% of cancer mortality, but whose underlying molecular mechanisms are incompletely understood. Tumor cell invasion includes the cross-talk of several pathways and little is known how these interactions affect this process in the tumor microenvironment. To analyse these cross-talk events, we have previously developed a method called combinatorial RNAi and investigated the contribution of different signalling intermediates downstream of ErbB2, i.e. Akt1 and MEK1 in the invasive phenotype of cells (Sahin et al, 2007). Recently, several miRNAs have been reported to be involved in the regulation of the invasive and metastasizing phenotype of cancer cells. We have demonstrated that miR-200 family members differentially regulate EGF-driven invasion of breast cancer cells (Uhlmann et al, 2010). Currently, we are studying the role of several miRNAs in migratory phenotypes of breast cancer cells.

3. Molecular cell biology of gastrointestinal stromal tumors (GIST)
Gastrointestinal stromal tumors (GISTs) are most frequent mesenchymal neoplasms of the gastrointestinal tract. KIT and PDGFR are the most commonly mutated RTKs which have crucial roles in the tumorigenesis of GIST. Recently, we have shown the contribution of miRNAs in disease development and tumor progression (Haller et al, 2010). Currently, we are examining the role of genetic and epigenetic factors in tumor progression of several GIST subtypes (based on mutation and localization) both in cell lines and patients.

Publications

Uhlmann S, Zhang JD, Schwäger A, Mannsperger H, RiazalhosseiniY, Burmester S, Ward A, Korf U, Wiemann S, Sahin Ö (2010). miR-200bc/429 cluster targets PLCγ1 and differentially regulates proliferation and EGF-driven invasion than miR-200a/141 in breast cancer. Oncogene. doi: 10.1038/onc.2010.201.

Haller F, von Heydebreck A, Zhang JD, Gunawan B, Langer C, Ramadori G, Wiemann S, Sahin Ö. (2010). Localisation- and mutation-dependent microRNA (miRNA) expression signatures in gastrointestinal stromal tumours (GISTs), with a cluster of coexpressed miRNAs located at 14q32.31. Journal of Pathology. 220(1):71-86.

Fröhlich H , Sahin Ö, Arlt D, Bender C, Beissbarth T. (2009). Deterministic Effects Propagation Networks for Reconstructing Protein Signaling Networks from Multiple Interventions. BMC Bioinformatics. 10:322.

Korf U, Löbke C, Sahin Ö, Haller F, Sültmann H, Arlt D, Poustka A. (2009). Reverse phase protein arrays (RPPA) for application-orientated cancer research (Review). PROTEOMICS - Clinical Applications. 3: 1140–1150.

Sahin Ö and Wiemann S. (2009) Functional genomics and proteomics approaches to study the ERBB-network in cancer. (Review). FEBS Lett 583(11):1766-71.

Sahin Ö, Fröhlich H, Löbke C, Korf U, Burmester, Majety M, Mattern J, Schupp I, Chaouiya C, Thieffry D, Poustka A, Wiemann S, Beissbarth T, Arlt D (2009) Modeling ERBB receptor-regulated G1/S transition to find novel targets for de novo trastuzumab resistance. BMC Syst Biol 3(1):1.

Sauermann M, Sahin Ö, Sültmann H, Hahne F, Blaszkiewicz S, Majety M, Zatloukal K, Füzesi L, Poustka A, Wiemann S, Arlt D (2008) Reduced expression of Vacuole membrane protein 1 (Vmp1) affects the invasion capacity of tumor cells. Oncogene 27(9):1320-6.

Löbke C, Laible M, Rappl C, Ruschaupt M, Sahin Ö, Arlt D, Wiemann S, Poustka A, Sültmann H, Korf U (2008) Contact-spotting of protein microarrays coupled with spike-in of normalizer protein permits time-resolved analysis of ERBB receptor signalling. Proteomics 8(8):1586-94.

Sahin Ö, Löbke C, Korf U, Appelhans H, Sültmann H, Poustka A, Wiemann S, Arlt D (2007) Combinatorial RNAi for quantitative protein network analysis. Proc Natl Acad Sci USA 104:6579-6584.

Arlt D, Sahin Ö, Korf U, Loebke C, Beißbarth T, Hahne F, Wiemann S, Poustka A (2006) Modeling breast cell cycle regulation - overcoming drug resistance Conf Proc IEEE Eng Med Biol Soc.1:40-3.

Collaborations

Y. Yarden, Weizmann Institute, Israel
N. Hynes, Friedrich Miescher Institute for Biomedical Research, Switzerland
F. Haller, Universitätsklinikum Freiburg, Germany
D. Thieffry, Université de la Méditerranée, France
T. Fehm / B. Gückel, Frauenklinik der Universität Tübingen, Germany
M. Cengiz Yakicier, Bilkent University, Turkey

Funding

German Federal Ministry for Science and Education (BMBF)
Wilhelm-Sander Stiftung
Deutsche Forschungsgemeinschaft (Deutsch-Israelisches Projekt - DIP)