Contact

Dr. med. Bruno Christian Köhler
bruno.koehler@nct-heidelberg.de

 

Research Group Cell Death Resistance

The scientific focus of the “Cell Death Resistance” group is the analysis and modulation of survival and cell death signaling in gastrointestinal tumors. The evasion of programmed cell death is a key feature of tumor cells and thus, the execution of cell death is the final inevitability of any tumor therapy. Even in the era of “omics” and the advent of personalized oncology, overcoming cell death resistance remains the critical step in tumor cell killing.

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Colorectal cancer, hepatocellular carcinoma and cholangiocarcinoma are in the focus of our research. We use three dimensional in vitro strategies, full competent ex vivo tissue culture systems, and mouse models to address urgent questions in a highly relevant field of cancer biology and translational oncology.

As part of the Clinical Research Unit KFO227 in Heidelberg, the group also aims to specify the role of anti-apoptotic Bcl-2 proteins for colorectal cancer development. We have proven a role of Bcl-2 proteins for carcinogenesis in the liver and colorectum, which reaches far beyond cell death regulation. In a translational approach our group harnesses cutting-edge in vitro, in vivo and ex vivo methodology to pave the way for a future clinical trial application of specific Bcl-2 protein inhibition.

In association with the Liver Cancer Center Heidelberg (LCCH) and in close collaboration with the largest European Liver Cancer Research Consortium (SFB/Transregio 209 Heidelberg/Hannover/Tübingen) the group has demonstrated novel key determinants of survival signaling and proliferation in the liver. We were able to prove a central role of the deubiquitinase CYLD for chronic liver injury and liver cancer development. Furthermore, we have shown a novel function of NFκB and the transcription factor RelB in liver fibrosis and hepatocarcinogenesis. The group aims to further unravel the mechanisms of aberrant NFκB activity in liver injury and hepatocarcinogensesis. We analyze approaches to sensitize liver cancer to therapy-induced cell death by manipulating NFκB signaling in the liver.

The identification of therapeutic strategies to overcome cell death resistance of cancer cells is a future goal of the group, since it has the potential to provide powerful tools to treat gastrointestinal cancer.

Our group has:

  • started to investigate the role of anaerobic tumor cell growth for therapy resistance and clinical course in colorectal carcinoma  (Deutsche Krebshilfe-funded project)
  • has for the first time demonstrated that non-canonical NFκB and its master transcription factor RelB drives liver fibrosis and hepatocarcinogenesis (DFG-funded project, Elßner et al. Gastroenterology 2019)
  • has been part of the Heidelberg Clinical Research Unit KFO 227 on Colorectal Cancer with a subproject addressing the role of anti-apoptotic Bcl-2 proteins for colorectal cancer development and progression. In the context of the KFO 227, the group i) has established various, intestine-specific Bcl-2 protein knockout mouse models unravelling novel functions of antiapoptotic Bcl-2 proteins (Scherr et al. Cell Death Diss 2016, Radakrishnan et al. Cancer Res. 2016) ii) has shown that suppression of anti-apoptotic Bcl-2 proteins regulates migration and invasion of colorectal cancer cells independent of cell death induction (Köhler et al. PLOS One 2014, PLOS One 2013)
  • proved that downregulation of the deubiquitinase CYLD i) contributes to apoptosis resistance of HCC cells (Urbanik et al. Int J Oncol 2011) and ii) triggers NF-kB activation and hepatocarcinogenesis in mice in vivo (Urbanik et al. J Hepatol 2012)
  • has demonstrated that increased apoptosis of hepatocytes coincides with strong hepatocyte proliferation resulting in spontaneous development of hepatocellular carcinoma in mice (DFG-funded project, Weber et al. Hepatology 2010).
  • has been associated to the largest European research consortium on HCC (SFB/TRR77 Heidelberg/Hannover) in 2010 with its project addressing the role of the anti-apoptotic Bcl-2 protein Mcl-1 for the pathophysiology of liver diseases (Vick et al. Hepatology 2009).
  • Paula Hoffmeister-Wittmann, Andreas Mock, Federico Nichetti, Felix Korell , Christoph E Heilig, Anna-Lena Scherr, Michael Günther, Thomas Albrecht, Eblina Kelmendi, Kaiyu Xu, Luisa Nader, Annika Kessler, Nathalie Schmitt, Sarah Fritzsche, Sofia Weiler, Benjamin Sobol, Albrecht Stenzinger, Stefan Boeck, Christoph B Westphalen , Klaus Schulze-Osthoff, Jörg Trojan, Thomas Kindler, Wilko Weichert, Karsten Spiekermann, Michael Bitzer, Gunnar Folprecht, Anna L Illert, Melanie Boerries, Frederick Klauschen, Sebastian Ochsenreither, Jens Siveke, Sebastian Bauer, Hanno Glimm, Benedikt Brors, Jennifer Hüllein, Daniel Hübschmann, Sebastian Uhrig, Peter Horak, Simon Kreutzfeldt, Jesus M Banales, Christoph Springfeld, Dirk Jäger, Peter Schirmacher, Stephanie Roessler, Steffen Ormanns, Benjamin Goeppert, Stefan Fröhling, Bruno C Köhler. Bcl-xL as prognostic marker and potential therapeutic target in cholangiocarcinoma. Liver Int. 2022 Dec;42(12):2855-2870.  doi: 10.1111/liv.15392. Epub 2022 Sep 14.
  • Benjamin Sobol, Osama Azzam Nieto, Emily Lara Eberlein, Anna-Lena Scherr, Lars Ismail, Annika Kessler, Luisa Nader, Maximilian Schwab, Paula Hoffmeister, Nathalie Schmitt, Dirk Jäger, Stefan Welte, Katharina Seidensaal, Petros Christopoulos, Christoph Heilig, Katharina Kriegsmann, Stefan Fröhling, Mark Kriegsmann, Jochen Hess, Bruno Christian Köhler. Specific Targeting of Antiapoptotic Bcl-2 Proteins as a Radiosensitizing Approach in Solid Tumors. Int J Mol Sci. 2022 Jul; 23(14): 7850. doi: 10.3390/ijms23147850. Published online 2022 Jul 16.
  • Anna-Lena Scherr, Andreas Mock, Georg Gdynia, Nathalie Schmitt, Christoph E. Heilig, Felix Korell, Praveen Rhadakrishnan, Paula Hoffmeister, Klaus H. Metzeler, Klaus Schulze-Osthoff, Anna L. Illert, Melanie Boerries, Jörg Trojan, Oliver Waidmann, Johanna Falkenhorst, Jens Siveke, Philipp J. Jost, Michael Bitzer, Nisar P. Malek, Loredana Vecchione, Ivan Jelas, Benedikt Brors, Hanno Glimm, Albrecht Stenzinger, Svetlana P. Grekova, Tobias Gehrig, Henning Schulze-Bergkamen, Dirk Jäger, Peter Schirmacher, Mathias Heikenwalder, Benjamin Goeppert, Martin Schneider, Stefan Fröhling, Bruno C. Köhler. Identification of BCL-XL as highly active survival factor and promising therapeutic target in colorectal cancer. Cell Death Dis. 2020 Oct; 11(10): 875. doi: 10.1038/s41419-020-03092-7. Published online 2020 Oct 17.
  • Anna-Lena Scherr, Adam Jassowicz, Anna Pató, Christin Elssner, Lars Ismail, Nathalie Schmitt, Paula Hoffmeister, Lasse Neukirch, Georg Gdynia, Benjamin Goeppert, Henning Schulze-Bergkamen, Dirk Jäger, Bruno Christian Köhler. Knockdown of Atg7 Induces Nuclear-LC3 Dependent Apoptosis and Augments Chemotherapy in Colorectal Cancer CellsInt J Mol Sci. 2020 Feb; 21(3): 1099. doi: 10.3390/ijms21031099. Published online 2020 Feb 7.
  • Elßner C, Goeppert B, Longerich T, Scherr AL, Stindt J, Nanduri LK, Rupp C, Kather JN, Schmitt N, Kautz N, Breuhahn K, Ismail L, Heide D, Hetzer J, García-Beccaria M, Hövelmeyer N, Waisman A, Urbanik T, Mueller S, Gdynia G, Banales JM, Roessler S, Schirmacher P, Jäger D, Schölch S, Keitel V, Heikenwalder M, Schulze-Bergkamen H, Köhler BC. Nuclear Translocation of RELB Is Increased in Diseased Human Liver and Promotes Ductular Reaction and Biliary Fibrosis in Mice. Gastroenterology. 2019 Mar;156(4):1190-1205.e14. doi: 0.1053/j.gastro.2018.11.018. Epub 2018 Nov 13.
  • Anna-Lena Scherr, Georg Gdynia, Mariam Salou, Praveen Radhakrishnan, Nicole Kautz, Adam Jassowicz, Christin Elssner, Walee Chamulitrat, Dirk Jaeger, Mathias Heikenwalder, Martin Schneider, Achim Weber, Wilfried Roth, Henning Schulze-Bergkamen and Bruno Christian Koehler. Bcl-xL is an oncogenic driver in colorectal cancer. Cell Death Dis. 2016 Aug 18;7(8):e2342. doi: 10.1038/cddis.2016.233.
  • Koehler BC, Jassowicz A, Scherr AL, Lorenz S, Radhakrishnan P, Kautz NElssner C, Weiss J, Jaeger D, Schneider M, Schulze-Bergkamen H. Pan-Bcl-2 inhibitor Obatoclax is a potent late stage autophagy inhibitor in colorectal cancer cells independent of canonical autophagy signaling. BMC Cancer. 2015 Nov 19;15:919. doi: 10.1186/s12885-015-1929-y.
  • Koehler BC, Scherr AL, Lorenz S, Urbanik T, Kautz NElssner N, Welte S, Lorenzo Bermejo J, Jäger D, Schulze-Bergkamen H. Beyond cell death - Antiapoptotic Bcl-2 proteins regulate migration and invasion of colorectal cancer cells in vitro. PLOS One 2013. 8(10):e76446.
  • Urbanik T, Boger RJ, Longerich T, Becker K, Ehrenberg KR, Hövelmeyer N, Hahn M, Schuchmann M, Jäger D, Waisman A, Wörns MA, Schulze-Bergkamen H. Liver specific deletion of CYLDexon7/8 induces severe biliary damage, fibrosis and increases hepatocarcinogenesis in mice. Journal of Hepatology. 2012. 57:995-1003.(Editorial: Gautheron J, Luedde T. A novel player in inflammation and cancer: The deubiquitinase CYLD controls HCC development. Journal of Hepatology 2012. 57(5):937-9.)
  • NCT Heidelberg School of Oncology (HSO2) Fellowship to Paula Hoffmeister-Wittmann

  • Deutsche Krebshilfe (2019-2022): „Maßgeschneiderte Therapie für anaerob und aerob wachsende Kolonkarzinome“

  • Brigitte und Dr. Konstanze Wegener Stiftung (2017-2020): „Die Bedeutung antiapoptotischer Bcl-2 Proteine in der Strahlentherapie von Kopf-Hals-Tumoren – Vom Mechanismus zur klinischen Anwendung“

  • Brigitte und Dr. Konstanze Wegener Stiftung (2015-2017): „Untersuchung der Wirksamkeit von Bcl-2 Inhibitoren in der Behandlung des kolorektalen Karzinoms ex vivo“

  • DFG (2014-2018): "Die Rolle der Deubiquitinase CYLD für Leberschädigung und Hepatokarzinogenese".

  • DFG: Subproject 8 of the Clinical Resarch Unit 227 (“Colorectal Cancer: From primary tumor progression towards metastases”; 2012-2017): „The role of anti-apoptotic Bcl-2 proteins for colorectal cancer development and progression“

  • DFG: Gerok Fellowship (SFB/TR209 “liver cancer”) to Bruno Köhler

  • Medical Faculty Heidelberg: Rahel-Gotein Straus Fellowship to Anna-Lena Scherr 2018-2019

  • Medical Faculty Heidelberg: Postdoc-Fellowship to Bruno C. Köhler 2012-2014

  • NCT Heidelberg School of Oncology (HSO2) Fellowship to Paula Hoffmeister-Wittmann

  • Preis der Deutschen Leberstiftung 2019 für Bruno Köhler

  • Gerok Fellowship ( SFB/TR209 “liver cancer”) to Bruno Köhler

  • Medical Faculty Heidelberg: Rahel-Gotein Straus Fellowship to Anna-Lena Scherr 2018-2019

  • Medical Faculty Heidelberg: Postdoc-Fellowship to Bruno C. Köhler 2012-2014

  • Promotionspreis der Diethelm-Stiftung an der Universitätsmedizin Mainz für Bruno C. Köhler 2012

Dr. Dr. Michael Dill, Experimental Hepatology, Inflammation and Cancer (F240), German Cancer Research Center (DKFZ), Heidelberg, Germany.

Dr. Rene-Filip Jackstedt, Cancer Progression and Metastasis (A013), German Cancer Research Center (DKFZ), Heidelberg, Germany.

Prof. Mathias Heikenwalder, Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Prof. Achim Weber, Institute of Surgical Pathology, University and University Hospital Zurich, Switzerland.

Prof. Martin Schneider,  Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Germany.

Prof. Jesus Banales,  IKERBASQUE,  San Sebastian, Spain.

PD Dr. Stephanie Roessler, Institute of Pathology, University Hospital Heidelberg, Germany.

Group leader:
PD Dr. Bruno C. Köhler

Bruno.koehler@nct-heidelberg.de

Postdoc:
Dr. Anna-Lena Scherr
Anna-lena.scherr@nct-heidelberg.de

Clinician Scientist:
Paula Hoffmeister Wittmann
Paula.hoffmeister-wittmann@nct-heidelberg.de

PhD Student.
Maximilian Schwab
Maximilian.Schwab@dkfz-heidelberg.de

MD Students:
Kaiyu Xu
Kaiyu.xu@stud.uni-heidelberg.de

Hanna Isele
Hanna.Isele@stud.uni-heidelberg.de

Technician:
Nathalie Schmitt, MSc
Nathalie.schmitt@nct-heidelberg.de

Eblina Kelmendi
Eblina.kelmendi@nct-heidelberg.de