E-Poster Presentation 33rd Lorne Cancer Conference 2021

Interrogating the cell-of-origin of BRCA1 mutant ovarian cancer to inform targeted strategies for cancer prevention (#171)

Rachel Joyce 1 2 , Bhupinder Pal 3 , Yunshun Chen 4 5 , Felicity Jackling 1 2 , Pradeep Tanwar 6 7 , Clare Scott 1 8 9 , Gordon Smyth 4 5 , Geoffrey Lindeman 1 10 11 , Jane Visvader 1 2
  1. ACRF Cancer Biology and Stem Cells Division, The Walter and Eliza Hall Institute, Parkville, VIC, Australia
  2. Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia
  3. Single Cell Cancer Genomics Laboratory, Olivia Newton John Cancer Research Institute, Heidelberg, VIC, Australia
  4. Bioinformatics Division, The Walter and Eliza Hall Institute, Parkville, VIC, Australia
  5. School of Mathematics and Statistics, The University of Melbourne, Parkville, VIC, Australia
  6. School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan , NSW, Australia
  7. Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
  8. Clinical Translation, The Walter and Eliza Hall Institute, Parkville, VIC, Australia
  9. Department of Obstetrics and Gynaecology, Royal Women's Hospital, Parkville, VIC, Australia
  10. Department of Medicine, The University of Melbourne, Parkville, VIC, Australia
  11. Parkville Familial Cancer Centre, Royal Melbourne Hospital and Peter MacCallum Cancer Cetnre, Parkville, VIC, Australia

Women who harbour mutations in BRCA1 have a cumulative breast cancer risk of approximately 70% and high grade serous ovarian cancer (HGSOC) risk of 44% to 80 years of age respectively1. There are few effective preventative therapy options for BRCA mutation carriers beyond prophylactic mastectomy and bilateral risk-reducing salpingo-oophorectomy, highlighting the need for prevention strategies. Recent studies have identified a RANK-positive luminal progenitor population of cells that are a putative cell-of-origin of BRCA1mut/+ breast cancer2; this population has proven targetable with the RANK ligand inhibitor denosumab and an international randomised phase III prevention study to assess the efficacy of denosumab treatment in preventative therapy for BRCA1 mutation carriers3 commenced in 2019. However, the aetiology of BRCA1mut/+ ovarian cancer and targetable molecular pathways for cancer prevention in these patients remains elusive. While the genesis of HGSOC is not fully understood, recent studies point to a cell within the PAX8+ secretory cell compartment of the fallopian tube epithelium (FTE) as the likely cell-of-origin4-6. We aim to characterise the epithelial differentiation hierarchy of the fallopian tube in wildtype mice, then identify targetable molecular pathway perturbations in FTE populations in a BRCA1-deficient mouse model. To this end, we have interrogated the Pax8+ compartment of the fallopian tube using candidate markers for flow cytometric fractionation identified by RNA-sequencing of EPCAM+ FTE cells paired with co-immunostaining. We have identified a unique population of EPCAM+PAX8+ cells that exhibit enhanced colony forming activity. Single cell RNA-sequencing has been employed to resolve unique Pax8+ subsets that are over-represented in preneoplastic BRCA1-mutant murine fallopian tube epithelium. Using a Pax8 promoter-driven mouse model of BRCA1-mutant HG-SOC which recapitulates the human disease, we are investigating Pax8+ subsets in ovarian cancer to identify putative targets for ovarian cancer prevention in BRCA1 mutation carriers.

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