Research Report 2010 - MDC

Peter M. SchlagStructure of the GroupGroup LeaderProf. Dr. Peter M. SchlagScientistsDr. Mathias DahlmannDr. Marion FehlkerDr. Johannes FritzmannDr. Wolfgang HaenschPD Dr. Wolfgang Kemmner(Group Leader Gene Profiling)Prof. Dr. Ulrike Stein (GroupLeader Tumor Metastasis)Surgical OncologyOur group has been focusing on the establishment of predictive and prognostic gene signaturesand expression profiles for analysis of metastases and drug resistance in colorectal cancer. Thedata provide the basis for novel therapeutic concepts in tumor treatment that are applicable andvalidated in the clinic. We were successful in identifying new metastases-associated genes, theirimportance for cancer metastases and their function in signaling pathways. We isolated andcharacterized the new gene MACC1, revealed S100A4/metastasin as novel target gene of theβ-catenin pathway and analyzed the interplay of BMP-4 and Bambi in the context of β-cateninsignaling. This provided insights into the tight association between early and late events of themetastasis process particularly in colorectal cancer, and opens opportunities for targetedtherapies. In the identification of patient-individualized gene expression profiles for improveddiagnosis and prediction regarding metastases formation and patient survival, the achievementswere made in close collaboration with the groups of W. Birchmeier and M. Lipp.In parallel to our achievements in understanding of new key regulators and molecularmechanisms in metastasis, we significantly advanced in the clinical development of local nonviralgene transfer for effective and applicable cancer gene therapy. We successfully performed a clinical"proof of principle“ phase I gene transfer trial at the ECRC using jet-injection for transfer of nakedDNA. In conclusion of this trial we made great efforts to further improve safety and efficiency ofnonviral vector systems and tested their therapeutic potential for clinical application.Classification of gastrointestinal carcinomas bygene expression profilingW. Kemmner, W. Qing, S. Förster, Q. Wang, P. M Schlag. Incooperation with M. Yashiro (Department of SurgicalOncology, Osaka City University Graduate School ofMedicine,Osaka, Japan), M. Vieth (Institute of Pathology,Klinikum Bayreuth, 95445 Bayreuth), P. Malfertheiner(Department of Gastroenterology, Hepatology andInfectious Diseases, Otto-von-Guericke UniversityMagdeburg, 39120 Magdeburg)The aim of this project was to find gene signatures thatallow a more precise differentiation of prognostic subtypesof gastrointestinal carcinomas. RNA was extractedfrom 60 colorectal, 72 gastric and 130 esophagealcancers and precancerous lesions respectively (e.g.GERD). After quality controls of the microarray data,ensuring the comparability of the different arrays, normalizationand data analysis was performed. Microarrayresults were validated by qRT-PCR analysis (TaqMan)and by immunohistochemistry.In each of the three cancer entities differentiallyexpressed genes were found which allow e.g. to discriminatebetween carcinoma subtypes. In the case ofesophageal neoplasias we were able to describe a newpotentially "high risk" group of Barrett's esophagus, ingastric carcinomas we described new candidate geneswith prognostic relevance and in colorectal cancer tissuewe identified a set of 42 genes which are significantlyupregulated in patients who are highly at risk forrecurrence after radical surgery. Most of the identified96 Cancer Research