Research Overview and Projects

The research group basically deals with colon cancer and pathological changes of the colon.

One main research focus lies on the identification of molecular mechanisms responsible for the development of tumors in a hereditary form of colorectal cancer (CRC) called Lynch syndrome. Lynch syndrome is caused by germline mutations in genes of the DNA mismatch repair (MMR) system which lead to MMR deficiency and the accumulation of mutations in the genome. Although patients with Lynch syndrome have a better prognosis compared to patients with sporadic colon cancer, associated tumors often show resistance to common chemotherapeutical treatment. In the long term, our research projects intend to facilitate diagnostics and to contribute to an improved individualized therapy of patients with Lynch syndrome / MMR deficiency.

A new research focus of our group aims to identify molecular patterns or changes in the microbiome responsible for the increased intestinal permeability, which occur in many patients during the development of a very serious disease of the liver - the acute-on-chronic liver failure (ACLF). The reasons for the development of ACLF are still largely unknown, but increased intestinal permeability can significantly trigger the progression of the disease.

Current projects

Phosphorylation of the human DNA mismatch repair protein MLH1 - What is the significance of this modification for DNA mismatch repair function?
15%-20% of all colon tumours exhibit defective MMR and show a significantly poorer response to common chemotherapies than MMR-proficient carcinomas. The most common cause of MMR loss is a defect in the MMR protein MLH1, which is involved not only in MMR but also in important MMR-independent signalling pathways, such as apoptosis. Recently, we identified an amino acid position in MLH1 that is phosphorylated by casein kinase II (CK2) and by which MMR function is blocked. This phosphorylation might govern a poor response to therapy in patients with colorectal carcinomas and is subject of current investigations.

Potential link between homologous recombination and mismatch repair pathways in colorectal carcinoma
Other germline mutations have been found in CRC patients within genes in the homologous recombination (HR) pathway which can lead to HR deficiency (HRD). A previous study showed that of 52,436 solid tumors assessed from 21 different cancer lineages, 17.4% showed HR mutations while 15% of the CRCs alone exhibited these mutations. When HRD occurs, the non-homologous end joining pathway (NHEJ) compensates and corrects DNA damage. In a study using a DNA-PKcs inhibitor to suppress the NHEJ pathway, HR-deficient cancer cells could be identified through catastrophic double strand break repair. This screen also identified cells with mutations in the MSH3 gene as particularly sensitive to NHEJ abrogation. Our group showed that MSH3 as well as MLH1 deficiency made cells sensitive to NHEJ inhibition after induced DNA damage in several CRC cell lines. This suggests that there may be a link between MMR deficiency and HR deficiency in CRC.

Characterization of MLH1- and SPTAN1-dependent signaling pathways as mediators of tumor progression in colon carcinoma
Compared to sporadic CRCs, MMR-deficient tumors show decreased metastatic behavior and respond altered to standard therapies and immune checkpoint inhibitors. We demonstrated that decreased MLH1 expression is associated with a reduction in cytoskeleton-associated Spectrin alpha II (SPTAN1) and leads to impaired migratory capacity. This project will characterize MLH1- and SPTAN1-dependent tumor-promoting genes and signaling pathways that lead to specific tumor progression of CRC and Lynch syndrome which might serve as biomarkers for personalized therapies.

Identification of triggers for dysfunctional intestinal barrier in acute-on-chronic liver failure
ACLF occurs in a background of chronic liver dysfunction and is associated with multiorgan failure and significant short-term mortality. Correlated with ACLF in some patients is an increased intestinal permeability which leads to serious bacterial infection and rapid death of these patients. The aim of this project is to identify alterations of proteins within damaged intestinal epithelial cells as potential triggers and to define therapeutically useful targets.

Technician

Virginia Nawrot
Virginia.Nawrot@unimedizin-ffm.de
Tel: +49 6301 87662

Zurück zur Homepage

Research Overview and Projects

• Heterogeneity in neuroendocrine tumors (cooperation with Prof. P. Wild, Senckenberg Institute for Pathology)
• Sinusoidal obstruction syndrome in patients with colorectal liver metastases (cooperation with PD Dr. Schreckenbach, Dept. of Surgery)
• Immune infiltrate in patients with upper GI cancer (joint project with IKF Frankfurt, Prof. Al-Batran, and Edinger Institute, Prof. Plate)

Staff

Doctoral students: Sharanya Pareek, Mira Hüttenschmidt, Nina Jungblut

Zurück zur Homepage

Research Overview and Projects

Infections and Infectious diseases constitute a major health problem in the field of hepatology. While earlier efforts of our Group focused on the handling of patients with viral hepatitis – especially with chronic hepatitis C – our latest efforts focus on the role, prevention and treatment of infections in patients with chronic liver disease (CLD) leading to acute decompensation (AD) and acute and chronic liver failure (ACLF).

Infections in CLD causing AD or ACLF: Infections in patients with CLD are the most frequent cause of AD and ACLF in the western world. ACLF, an AD characterized by concomitant organ failure is associated with extreme high short-term mortality (up to 70-90% with 90 days). Over the last decade, the number of multidrug-resistant bacteria (MDRO) isolated from cultures of patients with cirrhosis and infection has drawn the attention of clinicians and the hepatology community. Our group focuses on infections in patients with cirrhosis, the role of MDRO isolated identified in the patients (colonization and/or infection) and its influence on antibiotics used for treatment and infection prophylaxis.

Infections in liver disease: Another interest of our research group is the clinical impact of different viral and bacterial infections possibly causing acute or acute-on-chronic deterioration of liver function.

Chronic hepatitis C:  Chronic hepatitis C virus (cHCV) infection is still a major global health problem resulting in significant morbidity and mortality. The introduction of direct acting antivirals (DAA) has revolutionized HCV treatment and eradication can now be obtained in most patients. However, physicians are faced with an increasing number of patients with cHCV infection the are considered difficult-to-treat. Our group tackled several important questions of daily clinical routine including the handling and treatment of patients with HBV coinfection, elderly patients and patients with drug-abuse.