Introduction/Background High-grade serous ovarian cancer (HGSOC) is the most common subtype of ovarian cancer, characterised by vast genomic instability and heterogeneity and acquired resistance to platinum-based chemotherapy. A study characterising intra-tumoural heterogeneity (ITH) in HGSOC has identified variations in phenotypic responses to platinum treatment between different metastatic sites. In this study, we aim to investigate the effect of the local microenvironment on metastatic tumour cells’ response to treatment through development of 3D organotypic models constructed from omental stromal cells embedded in an extracellular matrix (ECM).
Methodology 3D models were assembled using normal omental stromal cells embedded in Collagen-I. Metastatic deposits were obtained from defined anatomical regions during upfront radical debulking surgery of advanced stage HGSOC patients. Tumour cells were extracted, cultured short-term, added to 3D models and treated with platinum for 24hrs. Flow cytometry was used to analyse tumour cell apoptosis within the models following treatment. To study variations in ECM composition by anatomical tumour location, ECM proteins were extracted for Mass Spectrometry analysis (4 patients, 5 samples per patient including primary, omentum, diaphragm, spleen, paracolic and rectal deposits).
Results Tumour cells cultured in 3D showed heterogeneity in response to platinum treatment, data showed a trend towards reduced response to treatment within 3D models compared to 2D (n=8). Changes in patterns of response to treatment between samples from 2D to 3D within the same patient was also demonstrated (n=5). Proteomic analysis displays heterogeneity in ECM composition across patients and different anatomical locations.
Conclusion Data will be correlated with our ongoing ITH study, including proteomic and copy-number analysis of corresponding disseminated tumour deposits, providing a definitive description of ITH and clonally evolved chemoresistance in HGSOC. Analysis of ECM composition from different anatomical sites will help develop 3D model-matrices further, incorporating more elements of the microenvironment and creating an experimental design better reflecting the in-vivo situation.
Disclosure Professor Christina Fotopoulou, COI: advisory boards and honoraria from Roche, Tesaro, Sequana, Olympus, Astra Zeneca.
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