Dissecting the Cellular and Molecular Regulation of Chemo-Resistance and Epithelial to Mesenchymal Transition in Human Ovarian Carcinoma

Ovarian carcinoma is the malignant transformation of ovarian or fallopian tube epithelial cells. High-grade serous carcinoma (HGSOC) diagnosis carries a 30% 5-year survival. The development of chemotherapy resistance is common leading to relapse of a resistant tumour. Due to inherent genetic/chromosomal instability in HGSOC, these tumours are multi-clonal leading to treatment resistance and metastasis. It was aimed to understand the clonal heterogeneity in HGSOC cell lines through single cell molecular and physiological dissection. Chapter 3 describes the use of single cell derived strains, single cell lineage tracking and single cell RNA sequencing of HGSOC cell line AOCS15 confirming a clonal fitness model of carboplatin resistance, establishing that molecular and physiological heterogeneity results in the development of platinum resistant clones in HGSOC. In Chapter 4, the chromatin proteome was compared between carboplatin treated resistant and sensitive single cell strains during the DNA synthesis phase. Major differences between sensitive and resistant clones included DNA repair, nuclear lamina, and DNA repair. In Chapter 5, the Bone Morphogenetic Protein (BMP) signalling pathway was targeted in combination therapy, Combination of DMH1 and Carboplatin increased the response of resistant clones through heightening replication stress by dampening the S/G2 checkpoint. In Chapter 6, BMP signalling correlated with an epithelial to mesenchymal transition (EMT) phenotype in ovarian cancer tumours. BMP inhibition in HGSOC cell lines led to down-regulation of EMT transcription factors and loss of cell migration in vitro and in vivo. In conclusion, the data presented confirms the presence of dynamic chemo-resistant subclones in ovarian cancer that may be underlined and targetable by BMP signalling