Organoids of epithelial ovarian cancer as an emerging preclinical in vitro tool: a review

Dumont, Sander; Jan, Žiga; Heremans, Ruben; Gorp, Toon Van; Vergote, Ignace; Timmerman, Dirk

doi:10.1186/s13048-019-0577-2

Cited by 27 publications

(20 citation statements)

References 43 publications

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“…Different 3D cell culture models have been applied to study EOC dissemination and response to therapy (recently reviewed in [39,54,55]), including the application of microfluidic technologies based on 3D spheroidbased sampling [54,56]. Since the fallopian tubes have been recently recognized as a potential primary origin of HGSOC [57], organoid cultures have been also produced from human and mouse fallopian tube epithelium [58][59][60].…”

Section: Discussionmentioning

confidence: 99%

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Development of a 3D functional assay and identification of biomarkers, predictive for response of high-grade serous ovarian cancer (HGSOC) patients to poly-ADP ribose polymerase inhibitors (PARPis): targeted therapy

et al. 2020

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Background Poly(ADP-ribose) polymerase inhibitors (PARPis) specifically target homologous recombination deficiency (HRD) cells and display good therapeutic effect in women with advanced-stage BRCA1/2-mutated breast and epithelial ovarian cancer (EOC). However, about 50% of high grade serous ovarian cancers (HGSOC) present with HRD due to epigenetic BRCA1 inactivation, as well as genetic/epigenetic inactivation(s) of other HR genes, a feature known as “BRCAness”. Therefore, there is a potential for extending the use of PARPis to these patients if HR status can be identified. Methods We have developed a 3D (spheroid) functional assay to assess the sensitivity of two PARPis (niraparib and olaparib) in ascites-derived primary cell cultures (AsPCs) from HGSOC patients. A method for AsPCs preparation was established based on a matrix (agarose), allowing for easy isolation and successive propagation of monolayer and 3D AsPCs. Based on this method, we performed cytotoxicity assays on 42 AsPCs grown both as monolayers and spheroids. Results The response to PARPis treatment in monolayer AsPCs, was significantly higher, compared to 3D AsPCs, as 88% and 52% of the monolayer AsPCs displayed sensitivity to niraparib and olaparib respectively, while 66% of the 3D AsPCs were sensitive to niraparib and 38% to olaparib, the latter being more consistent with previous estimates of HRD (40%–60%) in EOC. Moreover, niraparib displayed a significantly stronger cytotoxic effect in both in 3D and monolayer AsPCs, which was confirmed by consecutive analyses of the HR pathway activity (γH2AX foci formation) in PARPis-sensitive and resistant AsPCs. Global gene expression comparison of 6 PARPi-resistant and 6 PARPi-sensitive 3D AsPCs was indicative for the predominant downregulation of numerous genes and networks with previously demonstrated roles in EOC chemoresistance, suggesting that the PARPis-sensitive AsPCs could display enhanced sensitivity to other chemotherapeutic drugs, commonly applied in cancer management. Microarray data validation identified 24 potential gene biomarkers associated with PARPis sensitivity. The differential expression of 7 selected biomarkers was consecutively confirmed by immunohistochemistry in matched EOC tumor samples. Conclusion The application of this assay and the potential biomarkers with possible predictive significance to PARPis therapy of EOC patients now need testing in the setting of a clinical trial.

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Section: Discussionmentioning

confidence: 99%

“…[34][35][36]. Indeed, we and others have shown that 3D cultures display altered/reduced sensitivities to chemotherapeutic agents compared to 2D models, which may have a significant impact on the success of drug testing pipelines for cancer [36], including EOC [37][38][39][40].…”

Section: Introductionmentioning

confidence: 99%

Development of a 3D functional assay and identification of biomarkers, predictive for response of high-grade serous ovarian cancer (HGSOC) patients to poly-ADP ribose polymerase inhibitors (PARPis): targeted therapy

et al. 2020

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“…Tumoroids permit a faster culturing method, amenable to multiplexing a wider range of analysis tools in a pre-clinical setting. Several studies have shown promising results of tumoroid cultures mimicking histological morphology and drug responses across multiple cancer types [11][12][13][14][15]. However, a thorough analysis of the shifting stromal cell populations and the resulting effects on cancer cell behavior as a product of the culturing method have yet to be thoroughly investigated.…”

Section: Introductionmentioning

confidence: 99%

Comparative Molecular Analysis of Cancer Behavior Cultured In Vitro, In Vivo, and Ex Vivo

Hum

Sebastian

Gilmore

et al. 2020

Cancers

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Current pre-clinical models of cancer fail to recapitulate the cancer cell behavior in primary tumors primarily because of the lack of a deeper understanding of the effects that the microenvironment has on cancer cell phenotype. Transcriptomic profiling of 4T1 murine mammary carcinoma cells from 2D and 3D cultures, subcutaneous or orthotopic allografts (from immunocompetent or immunodeficient mice), as well as ex vivo tumoroids, revealed differences in molecular signatures including altered expression of genes involved in cell cycle progression, cell signaling and extracellular matrix remodeling. The 3D culture platforms had more in vivo-like transcriptional profiles than 2D cultures. In vivo tumors had more cells undergoing epithelial-to-mesenchymal transition (EMT) while in vitro cultures had cells residing primarily in an epithelial or mesenchymal state. Ex vivo tumoroids incorporated aspects of in vivo and in vitro culturing, retaining higher abundance of cells undergoing EMT while shifting cancer cell fate towards a more mesenchymal state. Cellular heterogeneity surveyed by scRNA-seq revealed that ex vivo tumoroids, while rapidly expanding cancer and fibroblast populations, lose a significant proportion of immune components. This study emphasizes the need to improve in vitro culture systems and preserve syngeneic-like tumor composition by maintaining similar EMT heterogeneity as well as inclusion of stromal subpopulations.

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“…In summary, several recent publications point that the in vitro cancer barrier is being transposed with the reconstruction of diversified tissue tumors on a plate, such as mammary gland, lungs, ovaries, and several others. [108][109][110][111][112]…”

Section: Cancerous Cellsmentioning

confidence: 99%

Historical evolution of spheroids and organoids, and possibilities of use in life sciences and medicine

Sakalem

Síbio

Costa

et al. 2021

Biotechnology Journal

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Background: An impressive percentage of biomedical advances were achieved through animal research and cell culture investigations. For drug testing and disease researches, both animal models and preclinical trials with cell cultures are extremely important, but present some limitations, such as ethical concern and inability of representing complex tissues and organs. 3D cell cultures arise providing a more realistic in vitro representation of tissues and organs. Environment and cell type in 3D cultures can represent in vivo conditions and thus provide accurate data on cell-to-cell interactions, and cultivation techniques are based on a scaffold, usually hydrogel or another polymeric material, or without scaffold, such as suspended microplates, magnetic levitation, and microplates for spheroids with ultra-low fixation coating. Purpose and scope:This review aims at presenting an updated summary of the most common 3D cell culture models available, as well as a historical background of their establishment and possible applications. Summary:Even though 3D culturing is incapable of replacing other current research types, they will continue to substitute some unnecessary animal experimentation, as well as complement monolayer cultures. Conclusion:In this aspect, 3D culture emerges as a valuable alternative to the investigation of functional, biochemical, and molecular aspects of human pathologies.

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Organoids of epithelial ovarian cancer as an emerging preclinical in vitro tool: a review

Cited by 27 publications

References 43 publications

Development of a 3D functional assay and identification of biomarkers, predictive for response of high-grade serous ovarian cancer (HGSOC) patients to poly-ADP ribose polymerase inhibitors (PARPis): targeted therapy

Development of a 3D functional assay and identification of biomarkers, predictive for response of high-grade serous ovarian cancer (HGSOC) patients to poly-ADP ribose polymerase inhibitors (PARPis): targeted therapy

Comparative Molecular Analysis of Cancer Behavior Cultured In Vitro, In Vivo, and Ex Vivo

Historical evolution of spheroids and organoids, and possibilities of use in life sciences and medicine

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