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Abstract High Grade Serous Ovarian Cancer (HGSOC) is the eighth cause of cancer-related mortality worldwide. Progress in eradicating this disease has been hampered by several factors, including the uncertainty about its tissues of origin, late diagnosis coupled to early dissemination through accumulation of ascitic fluid and extensive inter-patient variability. While being histopathologically homogeneous, HGSOC is characterized by several layers of heterogeneity that require the development of ad hoc research strategies and to focus on specific scales in order to deconvolve HGSOC pathogenetic mechanisms. In this context, our lab has previously shown that HGSOC can be derived both from the distal tract of the fallopian tube (fallopian tube epithelium, FTE) and the ovarian surface epithelium (OSE), with a prognostic impact for the tissue of origin and origin-specific molecular phenotypes, including an immune-suppressive response in the more aggressive OSE-derived subtype (Lo Riso, Villa et al. 2020), pointing at the role of tumor microenvironment in shaping therapeutical response. Moreover, we have also shown the role of ascitic fluid in sustaining the generation of single cell-derived metastatic ovarian cancer spheroids (sMOCS), that enrich for cancer stem-like cells, and allowing to identify a consistent intra-patient variability in response to carboplatin treatment (Velletri, Villa, Cilli, Barzaghi et al. 2022). To understand the specific impact of the tumor microenvironment in shaping HGSOC complexity, here we show an experimental framework aimed at the identification of the downstream effect of ascites in shaping cellular and molecular features of HGSOC. Here we leverage a newly generated single cell transcriptomic atlas, encompassing 1. 5 million cells from 79 patients derived from primary tumors, ascites and metastatic samples, to identify specific expression networks activated during the metastatization process. In parallel, we derive from bulk transcriptomic data the set of genes that are induced upon ascitic fluid supplementation in 2D and 3D in vitro models, that are coupled to model-specific phenotypes, including cell proliferation, stemness and invasiveness. These genes are then integrated in the single-cell derived metastasis-specific expression networks to identify the upstream regulators imputable to ascitic fluid exposure. The linked regulators and downstream effectors are then used to identify in the atlas cell populations whose expression landscape is directly affected by ascitic fluid. The identification of such cell populations will allow to highlight cell-to-cell interactions existing between i) different tumor subpopulations; ii) tumor and tumor-associated compartments, in both primary and metastatic samples, that can be ascribed to the presence of ascitic fluid. Moreover, the molecular characterization of these interacting populations will allow to identify novel targets, paving the way to the identification of novel therapeutical avenues for HGSOC patients. Citation Format: Pietro Lo Riso, Carlo Emanuele Villa, Bianca Barzaghi, Marta R. Sallese, Giulia Picco, Alessia Gatto, Ugo Cavallaro, Giuseppe Testa. Untangling the effect of ascites in shaping high grade serous ovarian cancer progression 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 Suppl₂): Abstract nr A105.
Riso et al. (Mon,) studied this question.