Abstract PR-009: Reconstructing the metastatic tumor microenvironment of high grade serous ovarian cancer using human multicellular in vitro models

Abstract

Abstract Effective treatment of high grade serous ovarian cancer (HGSOC) still represents a clinical challenge. This is partially due to poor understanding of the complexity of this disease and the highly immunosuppressive tumor microenvironment (TME) that makes HGSOC resistant to most of the newly discovered therapies. The lack of relevant and physiological human in vitro models represents a major issue as the development of new treatments are mostly based on mouse models that do not fully recapitulate the human disease. In this study, we developed 3-dimensional (3D) human multicellular in vitro models using as a template and validation, data collected in a previous study that ‘deconstructs’ the metastatic TME of HGSOC. Our human 3D in vitro pentaculture (five cell types) model is composed of patient-derived primary adipocytes, fibroblasts and mesothelial cells isolated from macroscopic normal omentum – the primary site of metastasis in HGSOC – of women undergoing a gynaeco-oncology surgery, combined with different high grade serous malignant cell lines and monocytes isolated from healthy individuals. We found that the peripheral blood monocytes were able to differentiate and polarize to macrophages in our model in a similar way that observed in human HGSOC omental metastasis. Interestingly, our pentaculture models self-rearrange at the cellular level in a different way depending on the malignant cell line used in the culture. RNAseq analysis of the pentacultures showed that the different cultures clustered according to the malignant cell line used suggesting that malignant cells have a major influence on the transcriptome of the TME. Moreover, we demonstrated that our pentacultures partially replicated human biopsies: some of the macrophage and fibroblast clusters identified in a previous scRNAseq experiment on human HGSOC biopsies were also found in the pentacultures. We then confirmed the presence of some these macrophages clusters at the protein level. Finally, these pentacultures reproduce some of the actions of macrophage modifying drugs that have previously been shown in vivo. In conclusion, the study of the immunosuppressive TME of HGSOC in these human 3D in vitro models allows us to identify the contribution of different cell types to tumor growth and spread and provides us a semi-high throughput platform for therapeutic screening. Citation Format: Beatrice Malacrida, Samar Elorbany, Eleni Maniati, Rachel Bryan-Ravenscroft, Sophie L.P. Skingsley, Florian Laforets, Ranjit Manchanda, Frances R. Balkwill. Reconstructing the metastatic tumor microenvironment of high grade serous ovarian cancer using human multicellular in vitro models [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr PR-009.