Kliniken & Institute … Institute Pathologisches Institut… Allgemeine Pathologie … Forschung Arbeitsgruppen AG Rössler

Tumor suppressor genes and the tumor microenvironment in hepatocellular carcinoma

Liver cancer is the third most common cause of cancer related death worldwide and more than 85% of liver carcinomas are hepatocellular carcinomas (HCC). The high mortality rate of HCC is mainly caused by metastasis or by de novo tumor formation in the diseased liver. Thus, liver inflammation, fibrosis and cirrhosis are the most important contributors to HCC development and progression. One of the key pathways is the interleukin-6 signaling pathway which facilitates the interplay between infiltrating immune cells and tumor cells in the tumor microenvironment of the liver. Although significant progress has been made in the HCC field, the molecular mechanisms and signaling pathways underlying HCC development and progression are still poorly understood. To better understand this aggressive tumor type, we are using cohort-based multi omics approaches, cell culture based analyses and animal experiments.

Using an integrative approach of high-resolution array-based comparative genomic hybridization (arrayCGH) and gene expression profiling, we identified tumor driver genes which are affected by genomic aberrations and functionally contribute to tumor progression (Roessler et al. Gastroenterology 2012). We found that chromosome 8p which exhibits the highest frequency (45%) of genomic copy number loss and is associated with poor outcome. A 10-gen signature was able to predict outcome in HCC and breast cancer. This signature contains the well characterized tumor suppressor DLC1 and two novel Tumor suppressor genes, SORBS3 and SH2D4A. In addition, we also identified tumor suppressive miRNA genes on chromosome 8p. Currently we are analyzing the molecular function of these tumor suppressor mRNA and miRNA genes.

Tumor-microenvironment interaction

It has been shown that tumor cells reside in a complex microenvironment of normal cells, cellular components and secreted small molecules. Tumor cells are not only effective in escaping from immune mediated eradication but they can induce tumor promoting factors in the tumor microenvironment. This interplay of tumor cells with components of their microenvironment can induce several molecular pathways, some of which may enhance tumor progression and lead to metastasis and poor outcome. Therefore, better understanding of the principles underlying tumor development and of the tumor-microenvironment interaction is critical to improve patient outcome. Multiple studies in liver cancer and other solid tumor types have demonstrated the critical involvement of inflammation, especially of interleukin-6 (IL-6) signaling during tumorigenesis and metastasis through an autocrine feedback mechanism.

We recently showed that the gene expression profiles of patients with chromosome 8p deletion are characteristic of the inhibition of interleukin-6 (IL-6) signal transduction (Ploeger et al. Hepatology, 2016). IL-6 signaling plays a crucial role in inflammation, tumor development and metastasis of HCC. Therefore, we investigated the role of chromosome 8p genes in IL-6 signaling and could demonstrate that the tumor suppressor genes SH2D4A and SORBS3 collaborate to inhibit STAT3/IL-6 signaling in HCC cells. Currently, the loss of a single compared to several tumor suppressor genes is investigated and the functional consequence of loss of several tumor suppressor genes determined.

Integration of multi-omics data and cohort-based analyses in cholangiocarcinoma

Cholangiocarcinoma (CCA) is a rare, highly aggressive and often fatal tumor of the bile ducts. According to their anatomical location, CCAs are classified as intrahepatic (iCCA), perihilar (pCCA) and distal CCA (dCCA). Cholelithiasis, primary sclerosing cholangitis (PSC), infection with the liver fluke parasites O. viverrini or C. sinensis have been described as risk factors in CCA. Our current research focuses on the molecular profiling of CCA using DNA methylation microarrays and genomic sequencing to identify patient subgroups. Recently, we were able to show that in intrahepatic CCA, four prognostically relevant patient subgroups can be distinguished by the integration of DNA methylation, genomic alterations, and mutations (Goeppert, Toth et al. Hepatology, 2019).

Development and progression of gallbladder carcinoma

Biliary tract cancer comprises gallbladder cancer (GBC) and cholangiocarcinoma (CCA). Overall GBC is a rare tumor entity with a prevalence of 2 per 100,000. However, in Native Americans the incidence is much higher with 23 per 100,000. General risk factors for GBC include female gender, age, ethnicity, genetic predisposition, cholelithiasis, chronic inflammation of the gallbladder and obesity. Due to the low prevalence in Western countries only very few studies on GBC exist. However, the low 2-year survival rate of less than 10% underpins the need for a better understanding for this disease. Therefore, we are using profiling technologies and cell culture systems to identify deregulated pathways in a well characterized cohort of GBC patients.

Development and progression of gallbladder carcinoma

Biliary tract cancer comprises gallbladder cancer (GBC) and cholangiocarcinoma (CCA). Overall GBC is a rare tumor entity with a prevalence of 2 per 100,000. However, in Native Americans the incidence is much higher with 23 per 100,000. General risk factors for GBC include female gender, age, ethnicity, genetic predisposition, cholelithiasis, chronic inflammation of the gallbladder and obesity. Due to the low prevalence in Western countries only very few studies on GBC exist. However, the low 2-year survival rate of less than 10% underpins the need for a better understanding for this disease. Therefore, we are using profiling technologies and cell culture systems to identify deregulated pathways in a well characterized cohort of GBC patients.

Selected publications

  1. Goeppert B, Toth R, Singer S, Albrecht T, Lipka DB, Lutsik P, Brocks D, Baehr M, Muecke O, Assenov Y, Gu L, Endris V, Stenzinger A, Mehrabi A, Schirmacher P, Plass C, Weichenhan D*, Roessler S*. Integrative analysis defines distinct prognostic subgroups of intrahepatic cholangiocarcinoma. Hepatology. 2019 May;69(5):2091-2106. PMID: 30615206. IF: 14.079. *contributed equally
  2. Goeppert B, Truckenmueller F, Ori A, Fritz V, Albrecht T, Fraas A, Scherer D, Silos RG, Sticht C, Gretz N, Mehrabi A, Bewerunge-Hudler M, Pusch S, Bermejo JL, Dietrich P, Schirmacher P, Renner M, Roessler S. Profiling of gallbladder carcinoma reveals distinct miRNA profiles and activation of STAT1 by the tumor suppressive miRNA-145-5p. Sci Rep. 2019 Mar 18;9(1):4796. PMID: 30886199. IF: 4.122.
  3. Ploeger C, Waldburger N, Fraas A, Goeppert B, Pusch S, Breuhahn K, Wang XW, Schirmacher P, Roessler S. Chromosome 8p tumor suppressor genes SH2D4A and SORBS3 cooperate to inhibit interleukin-6 signaling in hepatocellular carcinoma. Hepatology. 2016 Sept;64(3):828-42. PMID: 27311882. IF: 14.079.
  4. Roessler S*, Lin G*, Forgues M, Budhu A, Hoover S, Simpson RM, Wu X, He P, Qin LX, Tang ZY, Ye QH, Wang XW. Integrative genomic and transcriptomic characterization of matched primary and metastatic liver and colorectal carcinoma. Int J Biol Sci. 2015 Jan 1;11(1):88-98. PMID: 25552933. IF: 4.057. *contributed equally
  5. Roessler S, Long EL, Budhu A, Chen Y, Zhao X, Ji J, Walker R, Jia HL, Ye QH, Qin LX, Tang ZY, He P, Hunter KW, Thorgeirsson SS, Meltzer PS, Wang XW. Integrative genomic identification of genes on 8p associated with hepatocellular carcinoma progression and patient survival. Gastroenterology. 2012 Apr;142(4): 957-66. PMID: 22202459. IF: 20.773.

Full list of publications https://www.ncbi.nlm.nih.gov/pubmed/?term=Roessler+Stephanie+OR+Rössler+Stephanie

Funding

DFG (Deutsche Forschungsgesellschaft)

Wilhelm Sander-Stiftung

NCT Heidelberg School of Oncology

Brigitte Schlieben-Lange Program

DZIF (Deutsches Zentrum für Infektionsforschung)

Collaborations

Prof. Lars Zender, Division of Molecular Oncology of Solid Tumors, University Hospital Tuebingen

Dr. Xin Wei Wang, Liver Carcinogenesis Section, Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

Prof. Andreas Teufel, Division of Hepatology and Division of Clinical Bioinformatics, University Medical Center Mannheim

Internal Medicine, Gastrointestinal Oncology University Hospital Regensburg

Dr. Carsten Sticht, Zentrum für Medizinische Forschung, Mannheim

Prof. Jane McKeating, University of Oxford, UK

Group members

Dr. Stephanie Roessler (Group Leader)

Dr. Thomas Albrecht (Physician)

Eva Eiteneuer (Technician)

Angelika Fraas (Technician)

Jun Hu (PhD Student, CSC fellow)

Thorben Huth (PhD student)

Sarah Luiken (PhD Student)

Raisatun Nisa Sugiyanto (PhD student, maternity leave)

Felicia Truckenmüller (PhD Student)

Core Facility

Dr. Stephanie Roessler leads the section. For more details please visit:

Technologieplattform Lasermikrodissektion

Contact

Dr. rer. nat. Stephanie Rössler