Research Group at a Glance Hepatology (Heim Lab)

A Quick Overview of Our Research

Liver cancer, particularly hepatocellular carcinoma (HCC), is a prevalent and aggressive cancer with high mortality rates worldwide. Over 95% of HCCs develop on the background of chronic liver disease. Advancedstage HCC has limited treatment options, and a better understanding of the molecular and cellular pathogenesis of HCCs is urgently needed. Our research aims to address critical aspects of the personalized healthcare in HCC. Specifically, we are focusing on understanding the reasons for the highly heterogeneous courses of HCC, identifying biomarkers for tailored therapy allocation, and exploring the molecular mechanisms that lead to the development of drug resistance in tumor cells.

The most important underlying liver diseases that predispose to HCC are alcoholic liver disease, nonalcoholic fatty liver disease, chronic hepatitis B and chronic hepatitis C infection. Our lab has a longstanding research interest in viral hepatitis with a special focus on innate immune responses to viral hepatitis. We investigate the mechanisms behind disease stage transition during the natural course of chronic hepatitis B virus (HBV) infection.

Overall, our research group is dedicated to advancing the understanding of HCC and its underlying diseases, with the ultimate goal of developing more effective therapies and personalized treatment approaches.

Highlights, Breakthroughs and Current Projects

1. We have established a clinically annotated biobank of tumor and liver biopsies, as well as a blood bank, within the framework of a clinical study protocol. The use of human biopsies provides us with a unique opportunity to directly study the molecular and cellular pathogenesis of chronic liver diseases and HCC, and develop relevant preclinical research tools such as patient-derived tumor organoid and xenograft models.

2. We have generated a comprehensive molecular classification of HCC from patients across all disease stages and etiologies by employing a multiomics approach that included genomic, transcriptomic, proteomic and phosphoproteomic analyses. Our study offers a comprehensive overview of the molecular landscape of HCC and facilitates the identification of key pathways involved in the pathogenesis of HCC.

3. To address the lack of predictive biomarkers for therapy response, we have developed a clinically applicable predictive classifier for response to transarterial chemoembolization (TACE), the most widely used treatment for intermediatestage HCC. By integrating clinical, radiological, and genomics data into supervised machine-learning models, we identified predictive transcriptomic signatures for response to TACE in HCC patients. Furthermore, we complemented these findings using our biobank of HCC organoids to identify cancer cell intrinsic determinants of treatment response. Through this approach, we were able to uncover additional factors that mediate resistance to therapy, providing a more complete understanding of the underlying mechanisms.

4. For patients with advanced disease, the overall clinical benefit of the available HCC treatments is limited to a small fraction of patients. To address the demand for more effective therapies, we developed a preclinical drug discovery platform based on tumor organoid screening, with the aim to identify novel combination therapies for the treatment of advanced HCC.

5. Our biobank also includes liver biopsies from patients in various stages of chronic HBV (CHB) and chronic HCV (CHC) infection. Although there is a curative treatment for HCV infection, it seems that remnants of the HCV induced liver disease persist after resolution of the infection, contributing to an increased risk of HCC in these patients. Liver biopsies enable the investigation of the nature of the residual liver disease in an effort to better understand it and guide potential therapeutic interventions.

6. Currently, no curative treatment for chronic HBV (CHB) is available. CHB is characterized by different disease stages reflecting specific virus-host interactions. Clinically, CHB disease stages are identified mainly by peripheral markers of HBV infection. Disease stage associated intrahepatic mechanisms are much less understood, primarily due to the lack of suitable model systems. However, by using liver biopsies, we can investigate in detail the antiviral mechanisms that contribute to the control of viral replication in the different CHB disease stages