Introduction/Background*High Grade Serous Ovarian Cancer (HGSOC) frequently presents at an advanced stage with widespread disseminated disease. The majority of patients will ultimately relapse and develop platinum resistance. HGSOC is characterised by a high degree of genomic instability and heterogeneity which is not accounted for in current 2D cell line and murine models. 3D ex-vivo models such as patient-derived organoids (PDOs) are better able to recreate tumour architecture and microenviroment. In this study, we aim to generate multisite PDOs to demonstrate the spatial heterogeneity of cancer stem cells (CSCs) and responses to chemotherapy treatments in disseminated HGSOC.
Methodology Tumour cells were extracted from disseminated multisite tumours from chemo-naïve patients undergoing maximal effort cytoreductive surgery at Hammersmith Hospital, UK. PDOs were established by embedding tumour cells in basement membrane extract and in specialised organoid or R-Spondin-enriched media. PDOs were propagated and treated with standard-of-care chemotherapy drugs (cis- and carbo-platin, PARPi) to assess drug responses. PDOs were histologically processed for characterisation of tumour markers, and CSCs across multiple tumour sites and passages.
Result(s)*PDOs were established from multisite deposits (n=8 patients, mean = 7 tumours per patient, range = 4 – 10) and confirmed to be of HGSOC tumour origin. Response to R-Spondin-enriched media varied across sites and across patients, but was maintained over multiple passages. PDOs were assessed for expression of known CSC biomarkers (ALDH1, CD117, CD133, CD44). IC50 assays established for standard-of-care chemotherapy drugs demonstrated heterogenous responses to treatment.
Conclusion*PDOs demonstrated the heterogeneity of the CSC population, growth conditions, and drug responses, reflecting the complexity of HGSOC. Our data suggests that treatment regimens chosen based on drug response from a single tumour site may not be effective against other disseminated tumours. PDOs which include multiple metastatic sites may lead to the development of targeted and personalized treatment strategies which reflect the spatial heterogeneity of HGSOC.
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