Education and Training
Prof. Dr. Ursula Klingmüller heads the division “Systems Biology of Signal Transduction” at the German Cancer Research Center (DKFZ) in Heidelberg and is full professor at the University of Heidelberg in the faculty of biology. She studied biology at the Universities of Bayreuth and Heidelberg and worked as postdoctoral fellow in the groups of Lewis Cantley at Harvard Medical School and Harvey Lodish at the Whitehead Institute for Biomedical Research in Boston US. Subsequently, she headed independent junior groups at the Max-Planck-Institute in Freiburg and at the DKFZ in Heidelberg. She habilitated in molecular biology, genetics and cell biology and is since 2011 W3 professor at the University of Heidelberg.
Expertise
She combines the generation of quantitative time-resolved data with mathematical modeling to elucidate molecular mechanisms determining dynamic behavior of signal transduction pathways and intracellular information processing. To achieve this mass spectrometry-based methods are optimized to facilitate the absolute quantification of signal transduction proteins and their posttranslational modifications. Additionally, cancer related alterations in the composition of the extracellular matrix as well as in blood plasma proteins are quantified by mass spectrometry to establish biomarkers for early detection of cancer. Based on mechanism-based multiscale models therapy optimization as well as personalization of therapy decisions is supported.
- Systems medicine and signal transduction
- Identification of mechanisms contributing to lung cancer development and therapy resistance
- Mass spectrometry-based establishment of biomarkers in tissue or body liquids that can be utilized for early detection of lung cancer
Lung Cancer (LC)
- J. Duerr*, D. H. W. Leitz*, M. Szczygiel*, D. Dvornikov, S. G. Fraumann, C. Kreutz, P. K. Zadora, A. Seyhan Agircan, P. Konietzke, T. A. Engelmann, J. Hegermann, S. Mulugeta, H. Kawabe, L. Knudsen, M. Ochs, D. Rotin, T. Muley, M. Kreuter, F. J. F. Herth, M. O. Wielpütz, M. F. Beers, U. Klingmüller, M. A. Mall. Conditional deletion of Nedd4-2 in lung epithelial cells causes progressive pulmonary fibrosis in adult mice.
Nature Communications. 11: 2012, 2020. - D. Dvornikov, M. A. Schneider, S. Ohse, M. Szczygieł, I. Titkova, M. Rosenblatt, T. Muley, A. Warth, F. J. Herth, H. Dienemann, M. Thomas, J. Timmer, M. Schilling, H. Busch, M. Boerries, M. Meister, U. Klingmüller. Expression ratio of the TGFβ-inducible gene MYO10 is prognostic for overall survival of squamous cell lung cancer patients and predicts chemotherapy response
Science Reports, 8: 9517, 2018. - Lucarelli P*, Schilling M*, Kreutz C*, Vlasov A, Boehm ME, Iwamoto N, Steiert B, Lattermann S, Wäsch M, Stepath M, Matter MS, Heikenwälder M, Hoffmann K, Deharde D, Damm G, Seehofer D, Muciek M, Gretz N, Lehmann WD, Timmer J,Klingmüller U. Resolving the Combinatorial Complexity of Smad Protein Complex Formation and Its Link to Gene Expression.
Cell Systems, 6(1):75-89.e11, 2018. - *Melnik S, *Dvornikov D, Müller-Decker K, Depner S, Stannek P, Meister M, Warth A, Thomas M, Muley T, Risch A, Plass C, Klingmüller U, Niehrs C, Glinka A. Cancer cell specific inhibition of Wnt/β-catenin signaling by forced intracellular acidification.
Cell Discovery, 4:37, 2018. - Marwitz S, Depner S*, Dvornikov D*, Merkle R, Szczygieł M, Müller-Decker K, Lucarelli P, Wäsch M, Mairbäurl H, Rabe KF, Kugler C, Vollmer E, Reck M, Scheufele S, Kröger M, Ammerpohl O, Siebert R, Goldmann T,# Klingmüller U#. Downregulation of the TGFβ Pseudoreceptor BAMBI in Non-Small Cell Lung Cancer Enhances TGFβ Signaling and Invasion.
Cancer Research, 76(13):3785-801, 2016.
Dr. Barbara Helm | Postdoctoral fellow |
| |||
Dr. Piotr Zadora | Postdoctoral fellow |
| |||
Dr. Agus Rodriguez | Postdoctoral fellow |
| |||
Magdalena Szczygieł | Graduate student |
|
Lung Research - Projects
- Transforming growth factor-beta (TGFβ) plays a dual role in cancer: At early stages it acts as tumor suppressor and inhibits cell proliferation. Whereas at advanced stages TGFβ promotes epithelial to mesenchymal transition (EMT) and thereby contributes to tumor progression. The group is using a systems biology approach and showed that in lung fibrosis TGFβ signal transduction is hyperactivated (Duerr et al., Nat Commun 2020). First results point to major alterations in sensitivity of TGFβ signal transduction in lung cancer. Building on our mathematical model of TGFβ signal transduction (Lucarelli et al., Cell Syst 2018) and insights into the dynamics of gene expression (Dvornikov et al., Sci Rep 2018), the group is developing a targeted mass spectrometry approach to quantify TGFβ signal transduction components to enable patient stratification and prediction of innovative intervention strategies.
- Communication between tumor cells and fibroblasts in the tumor microenvironment influences tumor growth and responsiveness to therapeutic interventions. A very important, but not yet much studied aspect is the role of the extracellular matrix (ECM) that is primarily secreted by fibroblasts in response to TGFβ stimulation. By mass spectrometry the group showed that the composition of the extracellular matrix is different in lung cancer and tumor-free tissue and that these changes potentially occur early during cancer development. In vitro studies revealed that the composition of the ECM influences cell communication and might contribute to the development of therapy resistance.
- Inhibitors of tyrosine kinase activity (TKIs) target the epidermal growth factor receptor (EGFR) that is deregulated in lung cancer patients harboring an activating mutation in the EGFR. To understand mechanisms of resistance against TKIs, the group focuses on an interaction of EGFR with the receptor tyrosine kinases MET and AXL. Their analysis of dynamic properties by mathematical modeling revealed the importance of the ratio of the abundance of receptors. They are developing a targeted mass spectrometry approach to quantify the receptors also in patient tissue to validate the importance of the EGFR/MET expression ratio for responsiveness to EGFR TKIs.
- Lung cancer is usually uncovered at a stage when patients already suffer from metastatic disease. To improve early detection of lung cancer, the group pursues two strategies: (i) Since blood plasma is rather easily accessible, they are developing a mass spectrometry approach that copes with the broad range of protein abundance in blood and facilitates the detection of cancer relevant proteins. (ii) Patients with lung fibrosis or chronic obstructive pulmonary disease (COPD) have an elevated risk to develop lung cancer. The group utilizes samples from patients with comorbidities to establish by mass spectrometry mechanism-based biomarker patterns for early detection of lung cancer.
