Single-cell transcriptome analysis of HGSOC PDOs

High grade serous ovarian cancer (HGSOC) is the most aggressive subtype of ovarian cancer. HGSOC is characterized by high inter-tumoral and intra-tumoral heterogeneity, which contributes to chemotherapy resistance. To investigate the complexity underlying HGSOC heterogeneity, we carried out single-cell RNA transcriptomics of patient-derived organoids (PDOs) developed from biopsies of platinum-resistant and -sensitive HGSOC. We found that PDOs were characterized by subclusters of cells with different transcriptional states and patient-specific transcriptional signatures. Proliferative cell sub-populations exhibit expression of cell cycle and DNA damage response related genes, whereas non-proliferative sub-populations display interferon and inflammatory signatures. Moreover, sensitivity to platinum-based treatments was inversely correlated with the oxidative phosphorylation (OXHPOS) signature of PDOs, indicating a metabolic switch associated with chemoresistance. This study also indicates that neoadjuvant chemotherapy (NACT) directly up-regulates oncogenic and metabolic pathways that are involved in development of recurrence, such as the MYC and OXPHOS genes. Interestingly, NACT also induces the expression of MHC-II molecules. Overall, this study highlights the inter- and intra-tumoral heterogeneity of HGSOC PDOs and uncovers targetable vulnerabilities that can be exploited therapeutically to hijack chemoresistance.