Institut für Pathologie

Medizinische Universität Graz

Research Scope

We are aiming at generating novel animal models for steatohepatities and its concomitant diseases, i.e. liver fibrosis, cirrhosis and hepatocellular carcinoma (HCC) to imitate the ‘real’ human disease conditions.Using these valuable animal models, we are investigating the molecular mechanisms of human liver diseases with emphasis on several signal transduction pathways, e.g. NF-kB, JAK-STAT, mTOR signaling.

We are searching for good biomarkers relevant for the diagnosis, grading, treatment, and prognostic evaluation of human liver diseases (hepatitis, especially steatohepatitis, liver fibrosis, cirrhosis and HCC), colorectal cancer, and sarcomas – in particular endometrial stromal sarcoma (ESS) - by conducting in detail morphological and molecular characterization studies of human tissue specimens as well as cell biology studies.

Our group is working on elucidating the significance of circulating tumor cells and circulating tumor DNA in order to understand the metastasis process of various malignant diseases.

Digging into other new research grounds with so far unraveled processes, e.g. SUMOylation and the contribution of eukaryotic translation initiation factors in carcinogenesis.

Main Focus

(1) Biomarker research

To identify, characterise and target biomarkers in therapeutic approaches is the main goal of our reasearch group.Oncologically useful prognostic as well as predictive biomarkers are investigated in a multitude of reasearch projects.We cover the topics circulating tumor cells, circulating tumor DNA and tissue biomarkers for a variety of cancer entities of different organ systems. We are following unbiased approaches and educated guesses on particular signalling pathways where we have a long and specific expertise. In particular in the frame work of national and international collaborations with leaders in the field we are assesing novel biomarkers in cell culture, animal models including xenograft models, human primary and metastatic tumer tissue as well as blood.Our biomarker reasearch also focuses on non-oncological diseases like degenerativ disorders where all modern morphological and molecular tools are used in our daily practice.Thus we believe to represent a competent team being a good collaborator for academic partners and pharma industry in the steadily moving and extremly fascinating, exiting and challenging area of biomarker research.For example the IMI-financed EU-project OncoTrack (“Methods for systematic next generation oncology biomarker development“) is our most prestigious internationally well reccognized tumor biomarker project.

(2) Hepatitis, predominantly steatohepatitis and its concomitant diseases, hepatocellular carcinoma (HCC), Intermediate filaments (IFs)

Steatohepatitis

Steatohepatitis is a disease characterized by fatty liver, ballooning of hepatocytes, formation of Mallory-Denk bodies (MDBs), fibrosis and inflammation. It frequently leads to HCC formation. It is becoming a leading health problem, affecting a high percentage of world’s population. Therefore, it is crucial and meaningful to clarify its molecular mechanisms for improvements of future diagnosis and treatment. Steatohepatitis could be induced by hepatitis virus B and C (HBV and HCV) infection, chronic drug consumption and alcohol abuse, as well as autoimmune diseases. Depending on its inducing factors, steatohepatitis is subdivided into two types: alcoholic and non-alcoholic steatohepatitis (ASH/NASH) while non-alcoholic fatty liver disease (NAFLD) not automatically fulfills all criteria of NASH. However, its classification might not be definite because mixed inducing factors could co-exist. Herein, the functional links among acute and chronic inflammation, liver cell injury, tissue damage, regeneration and hepatocellular carcinogenesis represent one of our interests. To address these questions, certain features of steatohepatitis have been reproduced in our animal models by a variety of genetic modifications and treatments. Of note, models of spontaneously occurring steatohepatitis are available in our lab. There is a marked difference in the individual risk to develop steatohepatitis and to progress to cirrhosis. For example, steatohepatitis affects only 20% of heavy drinkers or 50% of obese type II diabetic patients. Several lines of evidence indicate that these differences are attributed to the existence of susceptibility and modifier genes that synergize with lifestyle factors. Consequently we are trying to define such susceptibility factors.  

Hepatocellular carcinoma (HCC) 
Our group currently focuses on various aspects of HCC. It is the most common primary liver cancer and the third most frequent cancer worldwide. Besides virus-induced HCC, steatohepatitis-driven HCC is becoming increasingly important. MDB formation, a typical feature of steatohepatitis, is characterized by keratins reorganization into aggregates and binding to p62 (sequestosome 1). Therefore, we are investigating the contribution of keratins and p62 to steatohepatitis and steatohepatitis-driven HCC. ? Intermediate filaments (IFs) Keratins 8/18 (K8/K18), the major intermediate filaments of digestive epithelial, are important in maintain cell structure and signal transduction. Their aggregates are typical features of several liver disorders, including ASH and NASH. p62 is an adaptor protein involved in signal transduction, e.g. TNFa-signalling leading to NF-kB activation, a well-known pathway important in liver caricinogenesis. It is also important in sequestraton of ubiquitinated proteins and the elimination of protein aggregates by autophagy. It is induced under certain stress conditions and specifically binds to misfolded and ubqitinated keratin, It is implicated that p62 fulfills multiple functions in the integration of cellular stress response with keratin aggregates in steatohepatitis and HCC. Our aim is to determine the impact of inborn and acquired alterations of K8/K18 architecture and its binding partner p62 in the occurrence and development of hepatitis and HCC, which will enhance our understanding of roles and interactions of K8/K18 cytoskeleton, p62 and specific modifier gene in HCC, and in turn leading to novel therapeutic approaches.

(3) Further oncological research

Besides HCC, other malignancies are our targets. In this regard, the main aims of research are to identify good biomarkers for diagnosis, grading, and prognostic evaluation of disease, as well as efficient treatments for the respective diseases. It includes:

  • Epithelial derived cancers of intra- and extra-hepatic bile ducts, gallbladder, pancreatic, urinary bladder, and colorectal cancer. The research on colorectal cancer is predominatly conduced in the framework of an European Union-funded project (ONCOTRACK, IMI-project). It aims at elucidating what is the significance of circulating tumor cells and circulating DNA in the metastatic process of colorectal cancer.
  • Mesenchymal derived tumor entities (sarcomas): uterine sarcoma, in particular endometrial stromal sarcoma (ESS).  
  • ITIH-proteins: We are currently investigating the impact of ITIH-proteins on several cancer entities. ITIH-proteins are known to have tumor-suppressive function in certain cancer types.
  • Brain tumors: predominantly gliomas
  • Neoplastic disorders of the lymphatic system: In this context we focus on the contribution of translational deregulation to the development and progression of lymphoma (Hodgkin’s and Non-Hodgkin’s lymphoma) and acute lymphoblastic leukemia.
  • Cancer of the lower respiratory tract: In this context we focus on the contribution of translational deregulation to the development and progression of cancer in the lower respiratory tract.

(4) Neuroscience research

Tightly conneceted to our Department of Neuropathology we are covering all aspect of modern neuropathological reasearch ranging from basic questions to applied clinically relevant goals. High quality morphological investigations are complemented by modern molecular tools as well as in vitro cell culture systems and various animal models.

We are interested in neurooncology, neuroimmunology and neurodegeneration.
In addition to brain tumors - in particular glimas - our neuropathological and neurobiological research is in parallel focused on mechanisms driving neurodegenerative disorders. This field of research is well collaborated with the Departments of Neurology, Neurosurgery and Pediatric Neurooncology of the Medical University Graz. Other internationally well recognized centers are also involved in this research. 

Group statement

The basis for our success is an excellent collaboration with our pre-clinical and clinical partners in Graz and externally.

  • TEXT
  • TEXT
  • TEXT
  • TEXT