Center for Molecular Medicine Cologne

Vangelis Kondylis - assoc. RG 12

Molecular hepatology

Abstract

Cell death is a central feature in chronic inflammatory diseases, including chronic liver disease (CLD).

It is increasingly clear that death of hepatocytes drives the development of liver disease by inducing inflammation, fibrosis and compensatory hepatocyte proliferation. This regenerative response in an inflammatory microenvironment is positively correlated with progression to end-stage cirrhosis and hepatocellular carcinoma (HCC), the most common form of liver cancer in humans (Figure 1).

Understanding the molecular mechanisms that regulate cell death could therefore provide new therapeutic options to treat these diseases.

Using genetic mouse models that recapitulate the major features of chronic liver disease (hepatocyte death, inflammation, fibrosis, compensatory proliferation, steatosis and HCC), in vitro culture systems and samples from human liver disease and HCC patients, our group aims to address:

  1. The role of different types of cell death in inflammatory liver disease and HCC progression, particularly focusing on RIP kinases 1 and 3 (RIPK1/RIPK3).
  2. The role of autophagy and the selective autophagy receptor Sqstm1/p62 in regulating cell death and HCC development. Autophagy-independent functions of p62 in regulating other signaling pathways, such as Keap1/Nrf2, mTORC1 and NF-κB, are also being investigated. 

Clinical and Medical Relevance

Chronic liver disease represents a growing worldwide burden. It most commonly develops upon chronic HBV and HCV infection, alcohol consumption and non-alcoholic steatohepatitis/metabolic syndrome and predisposes to liver carcinogenesis.

Liver damage is a driver of liver disease and our research aims at elucidating the molecular pathways that regulate hepatocyte and cholangiocyte death.

Our data suggest that compounds, such as RIPK1 inhibitors, could be beneficial for preventing progression to end-stage liver disease.

Project Related Publications

  1. Laurien L.,Nagata M., Schünke H., Delanghe T., Wiederstein J.L., Kumari S., Schwarzer R., Corona T., Krüger M., Bertrand M., Kondylis V., Pasparakis M. (2020). Auto-phosphorylation at serine 166 regulates RIP kinase 1 mediated cell death and inflammation. Nature Commun. In press.
  2. Krishna-Subramanian S., Singer S., Armaka M., Banales J.M., Holzer K., Schirmacher P., Walczak H., Kollias G., Pasparakis M., Kondylis V. (2019). RIPK1 and death receptor signaling drive biliary damage and early liver tumorigenesis in mice with chronic hepatobiliary injury. Cell Death Differ.26, 2710-26.
  3. Kondylis V., Pasparakis M. RIP kinases in liver cell death, inflammation and cancer.(2019). Trends Mol. Med.25, 47-63.
  4. Van T-M., Polykratis A., Straub B.K., Kondylis V., Papadopoulou N., Pasparakis M. (2017). Kinase-independent RIPK1 functions regulate hepatocyte survival and liver carcinogenesis. J Clin. Invest.127, 2662-2677.
  5. Wroblewski R., Armaka M., Kondylis V., Pasparakis M., Walczak H., Mittrücker H.W., Schramm C., Lohse A.W., Kollias G., Ehlken H. (2016). Opposing role of Tumor Necrosis Factor Receptor 1 signalling in T cell mediated hepatitis and bacterial infection in mice. Hepatology. 64, 508-521.
  6. Vlantis K., Wullaert A., Polykratis A., Kondylis V., Dannappel M., Schwarzer R., Welz P.S., Corona T., Walczak H., Weih F., Klein U., Kelliher M., Pasparakis M. (2016). RIPK1 mediated epithelial cell death causes Paneth cell loss and intestinal inflammation in mice with epithelial NEMO deficiency. Immunity. 44, 553-567.
  7. Piaggio F.*,Kondylis V.*, Pastorino F., Di Paolo D., Perri P., Cossu I., Schorn F., Marinaccio C., Murgia D., Daga A., Raggi F., Loi M., Emionite L., Ognio E., Pasparakis M., Ribatti D., Ponzoni M., Brignole C. (2016). A novel liposomal Clodronate depletes tumor-associated macrophages in primary and metastatic melanoma: Anti-angiogenic and anti-tumor effects. J. Control. Release.223, 165-177. *Equal contribution.
  8. Kondylis V., Polykratis A., Ehlken H., Ochoa-Callejero L., Straub B.K., Krishna-Subramanian S., Van T-M., Curth H.M., Heise N., Weih F., Klein U., Schirmacher P., Kelliher M., Pasparakis M. (2015). NEMO prevents steatohepatitis and hepatocellular carcinoma by inhibiting RIPK1 kinase activity mediated hepatocyte apoptosis. Cancer Cell.28, 582-598.
Dr. Vangelis Kondylis CMMC Cologne
Dr. Vangelis Kondylis

Institute for Pathology / RG location - CECAD Building

CMMC - assoc. Research Group

Publications - Vangelis Kondylis

Link to PubMed

Figure 1
Group Members

Farina Schneider