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Insights into spheroid formation: interaction of ovarian cancer cells with macrophage populations in the tumor microenvironment

Simone Pisano, Yajaira Sofia Jimenez, Paul Rees Orcid Logo, Jing Xiao, Deya Gonzalez Orcid Logo, Steve Conlan Orcid Logo, Bruna Corradetti

Journal of Translational Medicine, Volume: 23, Issue: 1, Start page: 1192

Swansea University Authors: Paul Rees Orcid Logo, Deya Gonzalez Orcid Logo, Steve Conlan Orcid Logo

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DOI (Published version): 10.1186/s12967-025-07162-2

Abstract

Background: Treating advanced ovarian cancer (OC) is challenging due to the immunosuppressive tumor microenvironment. This study investigates tumor-immune cell interactions using organotypic spheroid models that simulate the in vivo microenvironment. Methods: A dual-model spheroid system was establi...

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Published in: Journal of Translational Medicine
ISSN: 1479-5876
Published: Springer Nature 2025
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URI: https://cronfa.swan.ac.uk/Record/cronfa70807
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This study investigates tumor-immune cell interactions using organotypic spheroid models that simulate the in vivo microenvironment. Methods: A dual-model spheroid system was established combining serous adenocarcinoma SKOV-3 cells with monocytes, pro-inflammatory (M&#x3A6;1) or anti-inflammatory (M&#x3A6;2) macrophages, or their derived exosomes (EXOs). In Model A, immune cells or EXOs were co-seeded with tumor cells to replicate early heterotypic aggregation. In Model B, immune cells or EXOs were introduced 24 h post-spheroid formation to simulate immune infiltration into established spheroids. Spheroid morphology was quantified by diameter and circularity, while the distribution of immune cells and EXOs was assessed via fluorescence intensity profiling in 2D and 3D. epithelial-to-mesenchymal transition (EMT) marker expression was analyzed to assess tumor cell phenotypic changes. Results: Spheroids formed with SKOV-3 cells and ThP-1 monocytes developed a dense monocyte-enriched outer layer. Macrophage subtypes differentially influenced spheroid morphology: M&#x3A6;2 macrophages promoted the formation of multiple, loosely organized spheroids and increased N-cadherin expression, indicative of enhanced EMT. Similarly, M&#x3A6;-EXOs modulated EMT marker expression, underscoring the contribution of both direct cell interactions and paracrine signaling in regulating spheroid dynamics. Conclusions: Macrophages and their exosomes play a critical role in modulating the architecture and functional behavior of spheroids, reflecting two key aspects of OC progression: the formation of immune cell-enriched spheroids in ascitic fluid and tumor-immune interactions at peritoneal metastatic sites. 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spelling 2025-10-31T14:40:52.9030997 v2 70807 2025-10-31 Insights into spheroid formation: interaction of ovarian cancer cells with macrophage populations in the tumor microenvironment 537a2fe031a796a3bde99679ee8c24f5 0000-0002-7715-6914 Paul Rees Paul Rees true false bafdf635eb81280304eedf4b18e65d4e 0000-0002-1838-6752 Deya Gonzalez Deya Gonzalez true false 0bb6bd247e32fb4249de62c0013b51cb 0000-0002-2562-3461 Steve Conlan Steve Conlan true false 2025-10-31 EAAS Background: Treating advanced ovarian cancer (OC) is challenging due to the immunosuppressive tumor microenvironment. This study investigates tumor-immune cell interactions using organotypic spheroid models that simulate the in vivo microenvironment. Methods: A dual-model spheroid system was established combining serous adenocarcinoma SKOV-3 cells with monocytes, pro-inflammatory (MΦ1) or anti-inflammatory (MΦ2) macrophages, or their derived exosomes (EXOs). In Model A, immune cells or EXOs were co-seeded with tumor cells to replicate early heterotypic aggregation. In Model B, immune cells or EXOs were introduced 24 h post-spheroid formation to simulate immune infiltration into established spheroids. Spheroid morphology was quantified by diameter and circularity, while the distribution of immune cells and EXOs was assessed via fluorescence intensity profiling in 2D and 3D. epithelial-to-mesenchymal transition (EMT) marker expression was analyzed to assess tumor cell phenotypic changes. Results: Spheroids formed with SKOV-3 cells and ThP-1 monocytes developed a dense monocyte-enriched outer layer. Macrophage subtypes differentially influenced spheroid morphology: MΦ2 macrophages promoted the formation of multiple, loosely organized spheroids and increased N-cadherin expression, indicative of enhanced EMT. Similarly, MΦ-EXOs modulated EMT marker expression, underscoring the contribution of both direct cell interactions and paracrine signaling in regulating spheroid dynamics. Conclusions: Macrophages and their exosomes play a critical role in modulating the architecture and functional behavior of spheroids, reflecting two key aspects of OC progression: the formation of immune cell-enriched spheroids in ascitic fluid and tumor-immune interactions at peritoneal metastatic sites. This model provides a clinically relevant platform for preclinical testing of therapeutic strategies targeting peritoneal dissemination in OC. Journal Article Journal of Translational Medicine 23 1 1192 Springer Nature 1479-5876 Ovarian cancer, Immune cells, Macrophages, Exosomes, Spheroids, Metastatic processes, Image analysis 29 10 2025 2025-10-29 10.1186/s12967-025-07162-2 COLLEGE NANME Engineering and Applied Sciences School COLLEGE CODE EAAS Swansea University Another institution paid the OA fee Support for the study was provided by the Golfers Against Cancer Foundation to BC. 2025-10-31T14:40:52.9030997 2025-10-31T14:32:35.3135168 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science Simone Pisano 1 Yajaira Sofia Jimenez 2 Paul Rees 0000-0002-7715-6914 3 Jing Xiao 4 Deya Gonzalez 0000-0002-1838-6752 5 Steve Conlan 0000-0002-2562-3461 6 Bruna Corradetti 7 70807__35525__7e08d8e744954747ae450e7f3721c1a0.pdf 12967_2025_Article_7162.pdf 2025-10-31T14:32:35.3134467 Output 4019985 application/pdf Version of Record true © The Author(s) 2025. This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. true eng http://creativecommons.org/licenses/by-nc-nd/4.0/
title Insights into spheroid formation: interaction of ovarian cancer cells with macrophage populations in the tumor microenvironment
spellingShingle Insights into spheroid formation: interaction of ovarian cancer cells with macrophage populations in the tumor microenvironment
Paul Rees
Deya Gonzalez
Steve Conlan
title_short Insights into spheroid formation: interaction of ovarian cancer cells with macrophage populations in the tumor microenvironment
title_full Insights into spheroid formation: interaction of ovarian cancer cells with macrophage populations in the tumor microenvironment
title_fullStr Insights into spheroid formation: interaction of ovarian cancer cells with macrophage populations in the tumor microenvironment
title_full_unstemmed Insights into spheroid formation: interaction of ovarian cancer cells with macrophage populations in the tumor microenvironment
title_sort Insights into spheroid formation: interaction of ovarian cancer cells with macrophage populations in the tumor microenvironment
author_id_str_mv 537a2fe031a796a3bde99679ee8c24f5
bafdf635eb81280304eedf4b18e65d4e
0bb6bd247e32fb4249de62c0013b51cb
author_id_fullname_str_mv 537a2fe031a796a3bde99679ee8c24f5_***_Paul Rees
bafdf635eb81280304eedf4b18e65d4e_***_Deya Gonzalez
0bb6bd247e32fb4249de62c0013b51cb_***_Steve Conlan
author Paul Rees
Deya Gonzalez
Steve Conlan
author2 Simone Pisano
Yajaira Sofia Jimenez
Paul Rees
Jing Xiao
Deya Gonzalez
Steve Conlan
Bruna Corradetti
format Journal article
container_title Journal of Translational Medicine
container_volume 23
container_issue 1
container_start_page 1192
publishDate 2025
institution Swansea University
issn 1479-5876
doi_str_mv 10.1186/s12967-025-07162-2
publisher Springer Nature
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Biomedical Science{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Biomedical Science
document_store_str 1
active_str 0
description Background: Treating advanced ovarian cancer (OC) is challenging due to the immunosuppressive tumor microenvironment. This study investigates tumor-immune cell interactions using organotypic spheroid models that simulate the in vivo microenvironment. Methods: A dual-model spheroid system was established combining serous adenocarcinoma SKOV-3 cells with monocytes, pro-inflammatory (MΦ1) or anti-inflammatory (MΦ2) macrophages, or their derived exosomes (EXOs). In Model A, immune cells or EXOs were co-seeded with tumor cells to replicate early heterotypic aggregation. In Model B, immune cells or EXOs were introduced 24 h post-spheroid formation to simulate immune infiltration into established spheroids. Spheroid morphology was quantified by diameter and circularity, while the distribution of immune cells and EXOs was assessed via fluorescence intensity profiling in 2D and 3D. epithelial-to-mesenchymal transition (EMT) marker expression was analyzed to assess tumor cell phenotypic changes. Results: Spheroids formed with SKOV-3 cells and ThP-1 monocytes developed a dense monocyte-enriched outer layer. Macrophage subtypes differentially influenced spheroid morphology: MΦ2 macrophages promoted the formation of multiple, loosely organized spheroids and increased N-cadherin expression, indicative of enhanced EMT. Similarly, MΦ-EXOs modulated EMT marker expression, underscoring the contribution of both direct cell interactions and paracrine signaling in regulating spheroid dynamics. Conclusions: Macrophages and their exosomes play a critical role in modulating the architecture and functional behavior of spheroids, reflecting two key aspects of OC progression: the formation of immune cell-enriched spheroids in ascitic fluid and tumor-immune interactions at peritoneal metastatic sites. This model provides a clinically relevant platform for preclinical testing of therapeutic strategies targeting peritoneal dissemination in OC.
published_date 2025-10-29T05:31:45Z
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