Flash Talk and Poster Presentation 36th Lorne Cancer Conference 2024

Deciphering the cell-of-origin in BRCA1-derived ovarian cancer (#105)

Laura Marruecos 1 , Rachel Joyce 1 , Somi Kordafshari 1 , Amy Tsai 1 , Felicity Jackling 1 , Luuk Heitink 1 , Bhupinder Pal 2 , Lizhong Chen 3 , Gordon Smyth 3 , Geoffrey Lindeman 1 , Jane Visvader 1
  1. ACRF Cancer Biology and Stem Cells Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
  2. Olivia Newton-John Cancer Research Institute, Heidelberg, Vic, Australia
  3. Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia

Women who carry mutations in BRCA1 have a lifetime risk of 40% of developing ovarian cancer. Although high-grade serous ovarian cancers arising in BRCA1 mutation carriers are thought to originate from a rare stem cell population within the fallopian tube (FT) epithelium, these cells have not yet been identified. In the FT epithelium, ciliated cells with hair-like extensions for transporting fertilized ovules, coexist with secretory cells that produce growth factors and nutrients crucial for embryo viability. The stem cell is thought to reside within the secretory cell group. Our project is focused on identifying target cells in BRCA1-mutant FT that are predisposed to developing ovarian cancer. We employed a genetically engineered mouse model with deletions in the secretory cells of Brca1, Trp53 and Pten, which are amongst the most common mutations found in human ovarian cancer. We performed single-cell RNA sequencing (scRNA-seq) and conducted imaging at various stages during tumour formation to identify abnormal cell subsets and their molecular perturbations that drive tumour development. One cell subset was found to be expanded during the preneoplastic and hyperplastic stages in BRCA1/P53/PTEN-deficient mice. Additionally, this subset predominantly contributes to the formation of uterine and ovarian tumours. We are currently evaluating the tumorigenic potential of this cell subset using genome editing tools. Understanding the precise cellular origin of BRCA1-associated ovarian cancer has the potential to improve diagnostic and therapeutic strategies, allowing more effective and personalized treatments for affected patients.