High grade serous ovarian cancer (HGSOC) remains the leading cause of death from a
gynaecological malignancy. Disparity in response to treatment is observed, with most patients
showing sensitivity to platinum therapies initially, only to later relapse with acquired platinum
resistance. HGSOC is characterised by vast genomic instability and intra-tumoural
heterogeneity (ITH), contributing to the variation in patient response rates and making
development of longer term effective therapeutic approaches challenging.
In this project, I aimed to characterise the extent of spatial and temporal ITH in HGSOC,
profiling tumour samples from multiple disseminated metastatic sites to understand the link
between heterogeneity, response to treatment and patient outcome (n=49 patients, mean
number of tumour samples obtained per patient =9, range 4-15). This project identified
variations in apoptotic responses to platinum treatment between different metastatic sites
within patients in 2D cultures.
To investigate this observed phenotypic heterogeneity further and assess the impact of the local
tumour microenvironment on primary and metastatic HGSOC tumour cells’ treatment
responses, 3D organotypic models representing the peritoneal surface were designed. Variation
in response to treatment was observed in both 2D and 3D culture platforms with reduced
response to treatment seen in 3D organotypic cultures, highlighting the importance of more
complex culture systems. An optimal culture design to incorporate elements of the tumour
microenvironment in HGSOC was investigated through mass spectrometry analysis of ECM
protein composition and development of ex vivo tumour tissue slices. Analysis of ECM
composition showed broad heterogeneity across the patient cohort and between different
anatomical locations (n=4 patients, n=5 sample sites per patient).
Through the development of culture platforms which more closely represent the in vivo state,
the heterogeneity displayed in HGSOC can be further examined, leading to advancements in
discovery of potential diagnostic and prognostic biomarkers, testing of novel therapeutics and
improvements in patient outcomes.