![]() Here, we thus set out to establish a new method to isolate and grow in 3D the arguably most clinically relevant type of HGSOC cells, namely cells from metastatic ascites, taking advantage of their ability to grow in an anchorage-independent manner and harnessing this property for the establishment of clonal spheroids cultures in individual wells that could thus allow longitudinal tracing of their propagated features. Such polyclonal organoid platforms do not permit to align the molecular interrogation of individual cancer cells to their effective forming/propagating potential. For HGSOC patient-derived organoids have been described only recently, via protocols that aim at capturing and propagating the cellular heterogeneity of the original tumors from which they were derived. Organoids have been derived from several cancer types, enabling to probe the mutational and functional diversification of individual tumor cells at unprecedented resolution, such as in colorectal cancer. The development of new methods to robustly capture, from the original lesions and in a patient-specific manner, the cell subpopulations that maintain cancer growth is, thus, a key priority in the field.ģD organoid cultures have recently emerged as a powerful modeling approach for a variety of disorders to recapitulate salient features of the original tissue or organ and propagate in vitro relevant subpopulations of cells representative of the original in vivo complexity. Not only they do not allow to correlate molecular aberrations to clinical histories and are thus of no use to advance the precision oncology agenda, but they also fail to recapitulate the landscape of alterations observed in most primary tumor isolates. Īmong the technical hurdles that have hampered progress is the inadequacy of available ovarian cancer cell lines to model physiopathologically relevant aspects of the disorder. In addition, converging evidence points to the pharmacological resistance of specific subpopulations, varyingly referred to as cancer stem cells (CSCs) or cancer initiating cells (CICs), that can persist after chemotherapy and often remain quiescent for months in the peritoneal cavity from which they fuel renewed and/or continuous growth. The former relate, first of all, to the specific features of the anatomical localization that enable precocious dissemination through the abdomen, with metastatic ascites often concomitant with the first diagnosis. This is, in turn, rooted into the biology of the disease and the technical limitations that have so far hampered its investigation. ![]() High Grade Serous Ovarian cancer (HGSOC) constitutes a major unmet need in oncology as one of the most lethal gynecological cancers, due to the failure of surgery and chemotherapy at eradicating the disease, the ensuing nearly invariable recurrence and very limited therapeutical progress over the past decades. ![]() By enabling the enrichment of uniquely informative cell subpopulations from HGSOC metastasis and the clonal interrogation of their diversity at the functional and molecular level, this method provides a powerful instrument for precision oncology in ovarian cancer. By single cell RNA sequencing (scRNAseq) we define the cellular composition of metastatic ascites and trace its propagation in 2D and 3D culture paradigms, finding that sMOCS retain and amplify key subpopulations from the original patients’ samples and recapitulate features of the original metastasis that do not emerge from classical 2D culture, including retention of individual patients’ specificities. To overcome this roadblock, we present a new method to isolate and grow single cells directly from patients’ metastatic ascites, establishing the conditions for propagating them as 3D cultures that we refer to as single cell-derived metastatic ovarian cancer spheroids (sMOCS). High Grade Serous Ovarian cancer (HGSOC) is a major unmet need in oncology, due to its precocious dissemination and the lack of meaningful human models for the investigation of disease pathogenesis in a patient-specific manner.
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