Sir Peter MacCallum Department of Oncology - Theses
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ItemInvestigating the cell-of-origin of Serous Ovarian Tumours using single-cell transcriptomics( 2023-11)Serous ovarian cancer (SOC) is the deadliest type of female gynaecological tract cancer. Its cell of origin is currently debated. Finding the cell of origin of SOC could help with the development of novel diagnostic and screening biomarkers. I utilised single-cell transcriptomics bioinformatics methods to investigate cell types in normal human gynaecological tissues and serous ovarian tumours to investigate the cell of origin of serous ovarian cancer. Transcription profiles from single-nucleus and single-cell data generated from our lab and publicly available datasets of fresh human samples were evaluated in order to find and characterize epithelial cell populations in the premalignant and malignant states and derive their lineages. I identified novel rare progenitor cell populations in normal and premalignant fallopian tube and ovary. These stem cell populations expressed markers of stemness (ALDH1A3, ROR1, ROR2, PROCR) and serous ovarian cancer (CLDN1, WT1, MUC16). Since cancer is a tissue specific disease, I utilised these relevant normal tissue expression profiles to elucidate the identity of cell types in serous tumours based on the cell type identity preservation framework. Stromal cells previously annotated as cancer associated fibroblasts that were expressing mesenchymal and stemness markers were classified as part of the epithelial lineage in serous ovarian tumours. A differentiation trajectory indicated a linear epithelial lineage in all serous ovarian tumours irrespective of their grade. This lineage started from LGR5+ cancer stem cells progressing to ALDH1A3+ secretory progenitor cells, then to PAX8+ secretory cells and finally to FOXJ1+ ciliated cells. Functional evaluation of markers of precursor cell types indicated their quiescent and invasive properties and their possible role in angiogenesis. Here, I propose a stem cell model of serous ovarian tumour initiation and initial invasion.