Ovarian cancer (OC) is the most lethal gynaecological malignancy, with ~325,000 new cases and ~207,000 deaths annually. The most common and malignant subtype is high-grade serous ovarian cancer (HGSOC), which primary arises from fallopian tube (FT) secretory epithelium, and is often detected too late when the prognosis and treatment outcome are poor. Human microbiome is a community of trillions of microorganisms that inhabit our body, and their symbiosis with organism is crucial for maintaining health and homeostasis. Dysbiosis can have various negative effects, including carcinogenesis. Relationship between microbiome composition and OC is not yet fully elucidated, especially not at the level of intratumoral microbiome (oncobiome). However, it was shown that gut microbiome dysbiosis in mice can promote OC progression by activating the Hedgehog signalling pathway (HHP). We have shown that expression of transcription factors (TFs) GLI, the main effectors of HHP, was significantly downregulated in HGSOC tissue. Additionally, we discovered that some genes related to innate immunity such as S100A9, KRT16 and KRT17, are target genes of GLI TFs. Since it is well known that innate immunity plays a critical role in host protection against pathogens such as bacteria, we hypothesize that oncobiome, by downregulating HHP, debilitates innate immunity and thus enhances HGSOC development in its early phase.
This project aims to investigate in detail the interactions between the oncobiome and HHP in HGSOC. In fresh HGSOC and healthy FT tissue bacterial composition (bacteriome) will be determined by whole 16S rRNA gene sequencing, human and bacteria transcriptome (determined by dual RNA-seq) will show which bacterial genes are expressed and which human genes may be altered due to infection, while metabolomics will show which bacterial metabolites could cause malignant transformation of FT cells. Stool and vaginal swabs will be also sampled, to confirm the presence of bacteria, which may also enlighten the gut-FT axis and lead to the development of non-invasive diagnostic tests. An independent set of archival HGSOC tissues will be used to further confirm bacterial presence and protein levels of genes affected by these bacteria, what may also lead to the development of prognostic biomarkers. Finally, we will co-culture healthy FT cell lines with bacteria and modulate HHP to elucidate molecular mechanisms and cellular effects. Association between oncobiome, HHP and HGSOC opens new possibilities for prevention, early detection, patients’ stratification and treatment strategies.