Contact

 

Prof. Dr. Stefan Wiemann
Phone: +49 6221 424702/4701

E-mail: s.wiemann@DKFZ.de

 

 

We unravel...

 

molecular mechanisms of cancer to facilitate personalized medicine.

Division Molecular Genome Analysis

DKFZ
 
 
 

Our group/department has:

  • Within two National Genome Research Network (NGFN-Plus) projects “Cellular Systems Genomics” (coordinated by Stefan Wiemann) and “Environment-related Diseases” we conducted high- and low-throughput screens in gain- and loss-of-function settings in order to identify and validate candidate miRNAs regulating disease processes. Using a miRNA mimic library we have performed two whole genome screens to determine miRNAs regulating proinflammatory cytokine secretion and cell invasion/metastasis via modulation of the NF-κB and TGF signaling pathways (Keklikoglou et al., Oncogene 2012) and to elucidate miRNA-regulation of the EGFR-driven cell cycle network (Uhlmann et al., Mol Syst Biol 2012), respectively. These projects highlighted the miRNA-driven higher order regulation of gene expression and activities, where complementary signaling networks are co-regulated thus inducing consistent phenotypes. Within a German-Israeli collaboration, this work is extended to systematically unravel the impact of miRNA-regulation on signaling pathways in cancer metastasis.
  • Advancing precision medicine in the field of cancer is still curbed by the fact that a rational basis to predict treatment outcome is mostly missing. This applies also to trastuzumab, a therapeutic antibody that is administered in (metastasized) HER2+ breast cancer and has a 15-year history of clinical application. To unravel the intracellular molecular mechanisms behind trastuzumab activity, mathematical modeling employing ordinary differential equations (ODE) was combined with wet-lab experimentation. In this study we also included erlotinib, a small molecule drug inhibiting EGFR, in order to take reference to the crosstalk between the EGFR and ERBB2 receptor tyrosine kinases. Experimentation relied on systematic perturbation experiments to quantitatively assess the signaling-response towards drugs in the context of EGF signaling in a HER2+ cell line model. The data-based mathematical model provided evidence that trastuzumab locks the ERBB2 receptor in a quasi-active state with highly different consequences for ligand-dependent and ligand-independent signaling. Based on the mathematical model we propose perturbations that can be addressed by other drugs to turn a trastuzumab-resistant into a trastuzumab-susceptible breast cancer cell (Henjes et al., Oncogenesis 2012, Kaschek et al., in preparation). This work is continued with funding of the BMBF (e:Med HER2Low – 2014-2017) for subtypes not overexpressing the ERBB2 receptor.
  • Clinical material has been derived from a collaboration study with the NCT (Andreas Schneeweiss) and the Department of Pathology (Hans-Peter Sinn) at Heidelberg University (funding within NGFN, MedSys and e:Bio programs of the BMBF). In total, tumor samples from over 200 patients have been entered into the study thus far. For all patients primary tumor material is available, for the majority of patients blood samples have been taken during treatment and follow-up. In case of estrogen receptor positive (ER+) breast cancer, a precise risk classification is elemental for therapy-decision as patients with tumors of the histologic grade III are at higher risk of recurrence and require chemo-endocrine treatment, whereas patients of grade I are at lower risk and do not require chemotherapeutic regimen that are associated with severe side effects. Patients with histologic grade II profiles currently cannot be clearly classified in either low or high risk patients and, therefore, decision for the most suitable therapy is difficult. The aim of our study was to identify a protein biomarker signature that facilitates discriminative risk classification. A newly established biomarker selection workflow took histologic grade I and grade III profiles as surrogate endpoints and identified caveolin-1, NDKA, RPS6, and Ki-67 as highly specific markers for a predictive protein signature (Sonntag et al., Translational Proteomics 2014, EU patent EP12 154 916.6). In a Personalized Oncology project, we have utilized the RPPA proteomics platform for the targeted analysis of hormone-receptor positive breast cancer specimens by assessing the activation states of 12 cancer-relevant signaling pathways (Sonntag et al., in preparation).
  • The division has contributed to the systematic identification and cloning of human genes via its leading role in the German cDNA Consortium (1997-2008) as well as its involvement in the US Mammalian Gene Collection (MGC Project Team et al., Genome Res 2009), to the large-scale functional characterization of encoded proteins via cloning of open reading frames and their exploitation in systematic gain-of-function analysis e.g., (Simpson et al., Nat Cell Biol 2012), as well as to the establishment of the worldwide most comprehensive human ORF-resource in academia from the International ORFeome Collaboration (www.orfeomecollaboration.org).

2010 – 2013

  • Ward A, Balwierz A, Zhang JD, Kublbeck M, Pawitan Y, Hielscher T, Wiemann S, Sahin O: Re-expression of microRNA-375 reverses both tamoxifen resistance and accompanying EMT-like properties in breast cancer. Oncogene 2013, 32(9):1173-1182.
  • Uhlmann S, Mannsperger H, Zhang JD, Horvat EA, Schmidt C, Kublbeck M, Henjes F, Ward A, Tschulena U, Zweig K, Korf U, Wiemann S, Sahin O: Global microRNA level regulation of EGFR-driven cell-cycle protein network in breast cancer. Mol Syst Biol 2012, 8:570.
  • Simpson JC, Joggerst B, Laketa V, Verissimo F, Cetin C, Erfle H, Bexiga MG, Singan VR, Heriche JK, Neumann B, Mateos A, Blake J, Bechtel S, Benes V, Wiemann S, Ellenberg J, Pepperkok R: Genome-wide RNAi screening identifies human proteins with a regulatory function in the early secretory pathway. Nat Cell Biol 2012, 14(7):764-774.
  • Henjes F, Bender C, von der Heyde S, Braun L, Mannsperger HA, Schmidt C, Wiemann S, Hasmann M, Aulmann S, Beissbarth T, Korf U: Strong EGFR signaling in cell line models of ERBB2-amplified breast cancer attenuates response towards ERBB2-targeting drugs. Oncogenesis 2012, 1(7):e16.
  • Zhang JD, Koerner C, Bechtel S, Bender C, Keklikoglou I, Schmidt C, Irsigler A, Ernst U, Sahin O, Wiemann S, Tschulena U: Time-resolved human kinome RNAi screen identifies a network regulating mitotic-events as early regulators of cell proliferation. PLoS One 2011, 6(7):e22176.
  • BMBF e:Med („HER2Low“) 
  • e:Bio („SysMetBc“ and „MetastaSys“)
  • DFG Deutsch-Israelisches Projekt (DIP)
  • DKFZ HIPO

 

 

  •  Award of the European Society of Human Genetics to Peter Lichter (2012)