Genomics of Lung Cancer

Prof. Dr. med. Thorsten Stiewe

Thorsten Stiewe has been appointed Adjunct Faculty of the Institute for Lung Health for the area of Lung Cancer Genomics.

Thorsten Stiewe is a full professor for Molecular Oncology at the University of Marburg, Germany, and head of the Institute of Molecular Oncology and the Core Facility for Genomics. He studied medicine and chemistry and obtained his doctoral degree at the University of Essen, Germany, in 2000. After a postdoctoral training at the West German Cancer Center, Essen, Germany, he established a junior research group at the Rudolf Virchow Center, DFG Research Center for Biomedicine, at the University of Würzburg, Germany. In 2007, he was appointed professor for Molecular Oncology at Marburg University. In 2010, he also became head of the Genomics Core Facility. He is a member of the German Center for Lung Research (DZL), speaker of the Marburg Medical Core Facility Network (MedCFNet) and vice speaker of the LOEWE research cluster iCANx on crosstalk between tumors and the healthy and diseased lung microenvironment.

The Stiewe lab investigates the genomics of cancer with a particular focus on genetic alterations in tumor suppressor genes of the p53 family, which are the most frequently mutated genes in all the major subtypes of lung cancer. We investigate how the p53 family transcription factors are activated by environmental toxins, radiation and lung cancer driver oncogenes and how they crosstalk with other cellular signaling networks to protect from malignant transformation and metastatic spreading by reinstating tissue homeostasis. Using sophisticated CRISPR technologies for gene editing, we model lung cancer-associated gene mutations in vitro and in mice to dissect how genetic alterations switch tumor suppressors into tumor-promoting oncogenes and generate mutation-specific cancer phenotypes with distinct molecular signatures and corresponding vulnerabilities to classic and novel molecular therapies. Our research studies not only cell-intrinsic consequences of lung cancer mutations, but also non-cell-autonomous mechanisms by which mutated tumor suppressor genes crosstalk with other lung diseases to re-organize the lung tissue into a tumor-permissive and immuno-privileged microenvironment. A comprehensive understanding of individual lung cancer mutations is expected to reveal novels targets for personalized treatment approaches. Using mouse modelling, we test and optimize such targeting approaches for mutated tumor suppressors and identify biomarkers predictive for treatment responses.

More detailed information: www.uni-marburg.de/fb20/imo

Cooperative Projects in the ILH

• Rajkumar Savai: Elucidate mechanisms of crosstalk between cancer genomics and the tumor immune microenvironment during tumorigenesis and development of therapy resistance.
• Susanne Herold & Ana Ivonne Vazquez-Armendariz: Organoid models to study genetic aspects of lung cancer initiation and tumor microenvironmental crosstalk.
• Marek Bartkuhn: Functional annotation of the p53 mutome by saturating CRISPR mutagenesis for precision medicine.

Contact

Prof. Dr. Thorsten Stiewe

Institut für Molekulare Onkologie
und Genomics Core Facility
Zentrum für Tumor- und Immunbiologie
Philipps-Universität Marburg

Hans-Meerwein-Str. 3
D-35043 Marburg

Tel.: +49 (0)6421 28-26280
Fax: +49 (0)6421 28-24292

Email: stiewe@uni-marburg.de
Web: www.uni-marburg.de/de/fb20/bereiche/zti/imo

Ten most important publications:

1. Merle N, Elmshäuser S, Strassheimer F, Wanzel M, König AM, Funk J, Neumann M, Kochhan K, Helmprobst F, Pagenstecher A, Nist A, Mernberger M, Schneider A, Braun T, Borggrefe T, Savai R, Timofeev O, Stiewe T. (2022). Monitoring autochthonous lung tumors induced by somatic CRISPR gene editing in mice using a secreted luciferase. Mol Cancer 21, 191.
2. Gremke N, Polo P, Dort A, Schneikert J, Elmshäuser S, Brehm C, Klingmüller U, Schmitt A, Reinhardt HC, Timofeev O, Wanzel M, Stiewe T. (2020). mTOR-mediated cancer drug resistance suppresses autophagy and generates a druggable metabolic vulnerability. Nat Commun 11, 4684.
3. Kadosh E, Snir-Alkalay I, Venkatachalam A, May S, Lasry A, Elyada E, Zinger A, Shaham M, Vaalani G, Mernberger M, Stiewe T, Pikarsky E, Oren M, and Ben-Neriah Y (2020). The gut microbiome switches mutant p53 from tumour-suppressive to oncogenic. Nature 586, 133-138.
4. Klimovich B, Mutlu S, Schneikert J, Elmshäuser S, Klimovich M, Nist A, Mernberger M, Timofeev O, Stiewe T. (2019). Loss of p53 function at late stages of tumorigenesis confers ARF-dependent vulnerability to p53 reactivation therapy. Proc Natl Acad Sci USA 116, 22288-22293.
5. Timofeev O, Klimovich B, Schneikert J, Wanzel M, Pavlakis E, Noll J, Mutlu S, Elmshäuser S, Nist A, Mernberger M, Lamp B, Wenig U, Brobeil A, Gattenlöhner S, Köhler K, Stiewe T. (2019). Residual apoptotic activity of a tumorigenic p53 mutant improves cancer therapy responses. EMBO J 38, e102096.
6. Vogiatzi F, Brandt DT, Schneikert J, Fuchs J, Grikscheit K, Wanzel M, Pavlakis E, Charles JP, Timofeev O, Nist A, Mernberger M, Kantelhardt EJ, Siebolts U, Bartel F, Jacob R, Rath A, Moll R, Grosse R, Stiewe T (2016). Mutant p53 promotes tumor progression and metastasis by the endoplasmic reticulum UDPase ENTPD5. Proc Natl Acad Sci USA 113, E8433-E8442.
7. Wanzel M, Vischedyk JB, Gittler MP, Gremke N, Seiz JR, Hefter M, Noack M, Savai R, Mernberger M, Charles JP, Schneikert J, Bretz AC, Nist A, Stiewe T (2016). CRISPR-Cas9-based target validation for p53-reactivating model compounds. Nat Chem Biol 12, 22–28.
8. Schlereth K, Beinoraviciute-Kellner R, Zeitlinger MK, Bretz AC, Sauer M, Charles JP, Vogiatzi F, Leich E, Samans B, Eilers M, Kisker C, Rosenwald A, Stiewe T (2010). DNA binding cooperativity of p53 modulates the decision between cell-cycle arrest and apoptosis. Mol Cell 38, 356-68.
9. Cam H, Griesmann H, Beitzinger M, Hofmann L, Beinoraviciute-Kellner R, Sauer M, Huttinger-Kirchhof N, Oswald C, Friedl P, Gattenlohner S, Burek C, Rosenwald A, Stiewe T (2006). p53 family members in myogenic differentiation and rhabdomyosarcoma development. Cancer Cell 10, 281-93.
10. Stiewe T, Pützer BM (2000). Role of the p53-homologue p73 in E2F1-induced apoptosis. Nat Genet 26, 464-9.

Here you can find all ILH-publications

Funding