Co-Infection as a caus of ovarian cancer (CINOCA)

The clinical impact of bacteria-virus co-infections and the sequels of chronic infections are both poorly understood partly due to the difficulty in drawing conclusive etiological links years after the infectious assault. Here, we aim to investigate the contribution of chronic co-infections with human herpes viruses (HHVs) and the intracellular bacterium Chlamydia trachomatis (Ctr) to the onset of ovarian cancers. Recent epidemiological studies suggest a strong association of ovarian cancers with these infectious agents but surprisingly not with human papilloma virus, a known etiologic agent of cervical cancer. An important paradigm shift in recent years now firmly assigns the origin of ovarian cancer to the epithelial lining of the Fallopian tube (FT), a prime meeting site for chronic, often asymptomatic infections by both HHVs and Ctr, as well as the bacterium Neisseria gonorrhoeae (Ngo). Thus, mounting evidence of a connection between infection and ovarian cancer now warrants a careful analysis of the molecular events by which these pathogens may synergize in establishing their infectious niche and co-operatively promote malignant transformation. We intend to pursue research on three complementary levels. First, we aim to gain better understanding of the impact of FT-associated pathogens on the integrity of the host cell genome, which we know is severely affected by infection. This knowledge is important because DNA damage and de-regulation of the DNA damage response (DDR) are key drivers of cell transformation and cancer initiation. Second, we will exploit normal human FP epithelial cell cultures and long-term infection models in order to dissect the transformation processes in vitro. Finally, we will compare our in vitro observations to the in vivo scenario of human FTs, with the ultimate goal of identifying fingerprints of infection in the ovarian cancer genome. All this will be conducted by an interdisciplinary team of experts in virology, microbiology and molecular biology in concert with clinicians and bioinformaticians. These investigations will not only provide basic insights into the impact of infection on host cell integrity but generate clinically important information on the relative significance of FT-associated infections in ovarian cancer and may hence substantiate the clinical indication for salpingectomy as a measure of cancer prevention for women at risk. Within the CINOCA project, the contribution of the group led by Christoph Bock at the CeMM Research Center for Molecular Medicine (http://epigenomics.cemm.oeaw.ac.at) and the work of the Biomedical Sequencing Facility (http://biomedical-sequencing.at) focus on large-scale genome and epigenome mapping as well as on integrative bioinformatic analysis of the generated datasets.

This project was part of a European initiative studying the role of simultaneous infections with bacteria and viruses, and on their role for cancer development. Within a project consortium coordinated by the Max Planck Institute for Infection Biology (Berlin, Germany), the contribution of CeMM focused on the development and application of methods for the genome-wide analysis of gene regulation.The project has given rise to three main results, each documented by a scientific publication in a high-profile journal:1. We have developed a new ChIP-seq method for analyzing chromatin (ChIPmentation), which provides superior sensitivity and which works extremely well on low-input samples. This method makes it possible to study chromatin regulation in rare, biomedically relevant, cell types (https://dx.doi.org/10.1038/nmeth.3542).2. We have established single-cell RNA-seq at CeMM, bringing this powerful new technology to Austria. Using this technology, we have mapped gene transcription in those parts of the human pancreas that control insulin production (https://dx.doi.org/10.15252/embr.201540946).3. Focusing on chronic lymphocytic leukemia (CLL), a cancer for which an infection component has been suggested but not conclusively shown, we performed genome-wide mapping of the chromatin regulatory landscape and a detailed bioinformatic analysis of the different CLL disease subtypes (https://dx.doi.org/10.1038/ncomms11938.)In summary, this project has led to the development and validation of important tools for bio- medical research in Austria and beyond, which will facilitate future studies of specific disease.