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933 Transcriptomic heterogeneity in high grade serous ovarian cancer organoids
  1. James Clark,
  2. Christina Fotopoulou,
  3. Lydia Kondyliou,
  4. Catriona Dickie,
  5. Marc Lorentzen,
  6. Lucy Gater,
  7. Sofia Miron-Barroso,
  8. Jonathan Krell and
  9. Paula Cunnea
  1. Imperial College London, London, UK


Introduction/Background Given their genotypic and phenotypic correlation with in vivo tumours, patient-derived organoids (PDOs) are in increasing use as pre-clinical models for High Grade Serous Ovarian Cancer (HGSOC) and other malignancies. We sought to characterise inter- and intra-patient transcriptomic heterogeneity in PDOs from disseminated HGSOC and assess gene expression changes following cisplatin and PARP inhibitor treatment.

Methodology PDOs were established from multi-site tumours from patients undergoing primary cytoreductive surgery, tumour cells extracted, PDOs propagated using different media conditions (±R-spondin), and assessed for their responses to conventional and targeted therapeutics. PDO lines derived from 3 different patients were selected for growth in low dose cisplatin or rucaparib to model resistance. RNA-sequencing was performed to characterise transcriptomic differences between PDOs and following drug treatments.

Results 6 different PDO lines with different drug sensitivities were selected for RNAseq analysis, with baseline gene expression determined. 3 PDO lines from different tumour sites from the same case demonstrated significant intrapatient transcriptomic heterogeneity, with variations in a hallmark gene set enrichment analysis (GSEA), known HGSOC-related genes, cancer stem cell (CSC) genes, epithelial-mesenchymal transition (EMT) markers and drug transporters (p<0.05, logFC>0.5). 3 further PDO lines were grown in low doses of cisplatin or rucaparib, with increments in IC50 and AUC concentrations observed for cisplatin and rucaparib compared to controls (p<0.05). Differential gene expression following low dose treatment was observed across all 3 lines irrespective of IC50/AUC increments. Hallmark GSEA exhibited variation across multiple hallmarks following drug treatment. Increased expression of chemotherapy resistance genes, the drug transporter ABCA1 and genes associated with oxidative phosphorylation, CSC and EMT (p<0.05, logFC>0.5) was observed in response to cisplatin/rucaparib treatment.

Conclusion HGSOC PDOs demonstrated significant intra- and inter-patient transcriptomic heterogeneity, with further changes observed following drug treatments. Although further validation is required, these results provide insights into potential mechanisms of treatment resistance.

Disclosures None.

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