Brägelmann Lab

Mechanisms of Therapy Response and Tumor Evolution

Cancer is caused by accumulation of genetic and epigenetic changes. These enable tumor cells to acquire malignant properties like sustained proliferation and immune evasion. While mutations in single cells arise in a stochastic manner, those that provide fitness advantages lead to expansion of sub-clones following Darwinian evolutionary selection. This process depends on the genetic background, cell type of origin and environmental factors and leads to heterogeneity of cell populations within tumors as well as between patients. It moreover shapes the variability in response to cancer treatments and allows tumors to adapt during therapeutic stress. This in turn facilitates emergence of therapy resistance, a primary driver of cancer mortality.

Our research focus:

Understanding the molecular mechanisms of tumor development and therapy resistance evolution is vital to design precision medicine concepts and advance patient care. The Brägelmann Lab therefore aims to dissect the underlying drivers with a focus on lung and head and neck cancer. Combining patient-derived cancer cell lines, mouse models and analyses of patient samples provides a rich opportunity to uncover pathway-dependencies in meaningful experimental scenarios.

Utilizing model systems with defined genomic alterations and large scale functional genomics approaches, we aim to address the following translational research questions focusing on underlying genetic and transcriptomic determinants:

  • How response to cancer therapy is shaped by the genomic and epigenetic alterations emerging during tumor development.
  • How therapeutic stress rewires cancer signaling.
  • How relevant pathways can be identified and targeted therapeutically to exploit collateral sensitivities or synthetic lethality and prevent resistance. 

Our goals:

Our goal is to improve patient care by contributing to advanced cancer treatment strategies including personalized therapeutic concepts. We thus strive to unravel and understand the molecular mechanisms governing tumor evolution and therapy response using functional genomics, data-driven molecular biology and computational cancer research. We anticipate that our studies will aid in the rational design and optimization of new and existing treatment regimens.

Our approach:

To approach our goals we systematically investigate pre-clinical in vitro and in vivo model systems and patient samples combining methods from molecular biology, biochemistry, and bioinformatics. These include functional genomics such as genome-wide CRISPR screens, high-throughput sequencing, pharmacogenomics profiling and bioinformatics. We also maintain close collaborations with other research groups and clinician scientists to tackle these translationally relevant questions in an interdisciplinary fashion.

www.bragelmannlab.com

Principal Investigator

Dr. Johannes Brägelmann

Principal Investigator

johannes.braegelmann@uni-koeln.de

Johannes Brägelmann

Team

Philipp Baedecker
Philipp Baedecker

MD Student

Johannes Brägelmann
Dr. Johannes Brägelmann

Principal Investigator

Mareike Haarmann
Mareike Haarmann

PhD Student

Doris Helbig
PD Dr. Doris Helbig

Clinical Research Fellow

Coming soon…
Carina Lorenz

Student

Alessia Pantani
Alessia Pantani

MD Student

Anna Rosendahl
Anna Rosendahl

Student

Katharina Winkels
Katharina Winkels

Student

Most important publications

  1. Dammert MA*, Brägelmann J*, Olsen RR*, Böhm S*, Monhasery N, Whitney CP, Chalishazar MD, Tumbrink HL, Guthrie MR, Klein S, Ireland AS, Ryan J, Schmitt A, Marx A, Ozretic L, Castiglione R, Lorenz C, Jachimowicz RD, Wolf E, Thomas RK, Poirier JT, Büttner R, Sen T, Byers LA, Reinhardt HC, Letai A, Oliver TG, Sos ML. MYC paralog-dependent apoptotic priming orchestrates a spectrum of vulnerabilities in small cell lung cancer. Nature Comm 2019. *Authors contributed equally to this work.

  2. Michels S, Heydt C, van Veggel B, Deschler-Baier B, Pardo N, Monkhorst K, Rüsseler V, Stratmann J, Griesinger F, Steinhauser S, Kostenko A, Diebold J, Fassunke J, Fischer R, Engel-Riedel W, Gautschi O, Geissinger E, Haneder S, Ihle MA, Kopp HG, de Langen AJ, Martinez-Marti A, Nogova L, Persigehl T, Plenker D, Puesken M, Rodermann E, Rosenwald A, Scheel AH, Scheffler M, Spengler W, Seggewiss-Bernhardt R, Brägelmann J, Sebastian M, Vrugt B, Hellmich M, Sos ML, Heukamp LC, Felip E, Merkelbach-Bruse S, Smit EF, Büttner R, Wolf J. Genomic Profiling Identifies Outcome-Relevant Mechanisms of Innate and Acquired Resistance to Third-Generation Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy in Lung Cancer. JCO Precis Onc 2019 (3) pp1-14 

  3. Scheffler M, Ihle MA, Hein R, Merkelbach-Bruse S, Schee Al, Siemanowski J, Brägelmann J, Kron A, Abedpour N, Ueckeroth F, Schüller M, Koleczko S, Michels S, Fassunke J, Pasternack H, Heydt C, Serke M, Fischer R, Schulte W, Gerigk U, Nogova L, Ko YD, Abdulla DSY, Riedel R, Kambartel K, Lorenz J, Sauerland I, Randerath W, Kaminsky B, Hagmeyer L, Grohé C, Eisert A, Frank R, Gogl L, Schaepers C, Holzem A, Hellmich M, Thomas RK, Peifer M, Sos ML, Büttner R, Wolf J. K-ras Mutation Subtypes in NSCLC and Associated Co-occuring Mutations in Other Oncogenic Pathways. J Thorac Onc, 2019 vol. 14 (4) pp 608-616  

  4. Fassunke J, Müller F, Keul M, Michels S, Dammert MA, Schmitt A, Plenker D, Lategahn J, Heydt C, Brägelmann J, Tumbrink HL, Alber J, Klein S, Heimsoeth A, Dahmen I, Fischer RN, Scheffler M, Ihle MA, Priesner V, Scheel AH, Wagener S, Kron A, Frank K, Garbert K, Persigehl T, Püsken M, Haneder S, Schaaf B, Rodermann E, Engel-Riedel W, Felip E, Smit EF, Merkelbach-Bruse S, Reinhardt HC, Kast SM, Wolf J, Rauh D, Büttner B, Sos ML. Overcoming EGFRG724S-mediated osimertinib resistance through unique binding characteristics of second-generation EGFR inhibitors. Nature Communications, 2018 vol. 9 (1) p. 4655   

  5. Brägelmann J, Lorenzo Bermejo J.  A comparative analysis of cell-type adjustment methods for epigenome-wide association studies based on simulated and real data sets. Letter in Bioinf (2018)   

  6. Plenker D, Bertrand M, de Langen AJ, Riedel R, Lorenz C, Scheel AH, Müller J, Brägelmann J, Daßler-Plenker J, Kobe C, Persigehl T, Kluge A, Wurdinger T, Schellen P, Hartmann G, Zacherle T, Menon R, Thunnissen E, Büttner R, Griesinger F, Wolf J, Heukamp L, Sos ML, Heuckmann JM. Structural Alterations of MET Trigger Response to MET Kinase Inhibition in Lung Adenocarcinoma Patients. Clin Cancer Res 2018; 24(6):1337–1343.    

  7. Brägelmann J*, Dammert MA*, Dietlein F*, Heuckmann JM*, Choidas A*, Böhm S, Richters S, Basu D, Tischler V, Lorenz C, Habenberger P, Fang Z, Ortiz-Cuaran S, Leenders F, Eickhoff J, Koch U, Getlik M, Termathe M, Sallouh M, Greff Z, Varga Z, Balke-Want H, French CA, Peifer M, Reinhardt HC, Őrfi L, Kéri G, Ansén S, Heukamp LC, Büttner R, Rauh D, Klebl BM, Thomas RK, Sos ML. Systematic Kinase Inhibitor Profiling Identifies CDK9 as a Synthetic Lethal Target in NUT Midline Carcinoma. Cell Reports 2017; 20(12): 2833–2845 *Authors contributed equally to this work. 

  8. Mollaoglu G*, Guthrie MR*, Böhm S*, Brägelmann J*, Can I, Ballieu PM, Marx A, George J, Heinen C, Chalishazar MD, Cheng H, Ireland AS, Denning KE, Mukhopadhyay A, Vahrenkamp JM, Berrett KC, Mosbruger TL, Wang J, Kohan JL, Salama ME, Witt BL, Peifer M, Thomas RK, Gertz J, Johnson JE, Gazdar AF, Wechsler-Reya RJ, Sos ML, Oliver TG. MYC Drives Progression of Small Cell Lung Cancer to a Variant Neuroendocrine Subtype with Vulnerability to Aurora Kinase Inhibition. Cancer Cell 2017; 31(2): 270–285 *Authors contributed equally to this work.  

  9. Plenker D, Riedel M, Brägelmann J, Dammert MA, Chauhan R, Knowles PP, Lorenz C, Keul M, Bührmann M, Pagel O, Tischler V, Scheel AH, Schütte D, Song Y, Stark J, Mrugalla F, Alber Y, Richters A, Engel J, Leenders F, Heuckmann JM, Wolf J, Diebold J, Pall G, Peifer M, Aerts M, Gevaert K, Zahedi R, Buettner R, Shokat KM, McDonald NQ, Kast SK, Gautschi O, Thomas RK, Sos ML.  Drugging the catalytically inactive state of RET kinase in RET-rearranged tumors. Science Translational Med 2017. Vol 9 (394).

  10. Brägelmann J*, Klümper N*, Offermann A*, von Mässenhausen A, Böhm D, Deng M, Queisser A, Sanders C, Syring I, Merseburger AS, Vogel W, Sievers E, Vlasic I, Carlsson J, Andrén O, Brossart P, Duensing S, Svensson MA, Shaikhibrahim Z, Kirfel J, Perner S. Pan-Cancer Analysis of the Mediator Complex Transcriptome Identifies CDK19 and CDK8 as Therapeutic Targets in Advanced Prostate Cancer.  Clin Cancer Res 2017; 23(7): 1829–1840. *Authors contributed equally to this work.