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.

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/department 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).
  • 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 N, Elssner 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 N, Elssner 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.)
  • 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
  • Award of the "Deutschen Leberstiftung 2019" to 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" to Bruno C. Köhler 2012