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Cisplatin resistance alters ovarian cancer spheroid formation and impacts peritoneal invasion

Lewis Francis Orcid Logo

Frontiers in Cell and Development Biology

Swansea University Author: Lewis Francis Orcid Logo

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DOI (Published version): 10.3389/fcell.2025.1450407

Abstract

Epithelial ovarian cancer (EOC) is an aggressive and lethal gynaecologic malignancy due to late diagnosis and acquired resistance to chemotherapeutic drugs, such as cisplatin. EOC metastasis commonly occurs through the extensive dissemination of multicellular aggregates, formed of cells originally s...

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Published in: Frontiers in Cell and Development Biology
Published: Frontiers
URI: https://cronfa.swan.ac.uk/Record/cronfa68707
first_indexed 2025-01-17T13:35:10Z
last_indexed 2025-01-17T20:44:40Z
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spelling 2025-01-17T13:36:49.7031177 v2 68707 2025-01-17 Cisplatin resistance alters ovarian cancer spheroid formation and impacts peritoneal invasion 10f61f9c1248951c1a33f6a89498f37d 0000-0002-7803-7714 Lewis Francis Lewis Francis true false 2025-01-17 MEDS Epithelial ovarian cancer (EOC) is an aggressive and lethal gynaecologic malignancy due to late diagnosis and acquired resistance to chemotherapeutic drugs, such as cisplatin. EOC metastasis commonly occurs through the extensive dissemination of multicellular aggregates, formed of cells originally shed from the primary ovarian tumour, within the peritoneal cavity.However, little is known about how cisplatin resistance (CR) alters the biophysical properties of EOC multicellular aggregates and how this impacts metastasis. In this interdisciplinary study, light and atomic force microscopy was used, alongside quantitative gene and protein expression analysis, to reveal distinct differences in the biophysical properties of CR spheroids, which correlated with altered protein expression of plasminogen activator inhibitor-1 (PAI-1) and Tenascin-C. CR SKOV3 spheroids (IC50: 25.5 µM) had a significantly greater area and perimeter and were less spherical, with a reduced Young's modulus, (p< 0.01) compared to parental (P) SKOV3 spheroids (IC50: 5.4 µM). Gene expression arrays revealed up-regulation of genes associated with cell adhesion, ECM and epithelial-to-mesenchymal transition (EMT) in CR spheroids, while immunofluorescence assays demonstrated increased protein expression of PAI-1 (p<0.05; implicated in cell adhesion) and reduced protein expression of Tenascin-C (p<0.01; implicated in elasticity) in CR spheroids compared to P spheroids. Furthermore, the CR spheroids demonstrated altered interactions with a surface that mimics the peritoneal liningsurface post mesothelial clearance (Matrigel). CR spheroids were significantly less adhesive with reduced disaggregation on Matrigel surfaces, compared to P spheroids (p<0.05), while CR cells were more invasive compared to P cells. The combined characterisation of the biophysical and biological roles of EOC multicellular aggregates in drug resistance and metastasis highlight key proteins which could be responsible for altered metastatic progression that may occur in patients that present with cisplatin resistance. Journal Article Frontiers in Cell and Development Biology Frontiers 0 0 0 0001-01-01 10.3389/fcell.2025.1450407 COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University External research funder(s) paid the OA fee (includes OA grants disbursed by the Library) MR/X502686/1 ; MC_PC_19053 2025-01-17T13:36:49.7031177 2025-01-17T13:33:19.3937186 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Lewis Francis 0000-0002-7803-7714 1
title Cisplatin resistance alters ovarian cancer spheroid formation and impacts peritoneal invasion
spellingShingle Cisplatin resistance alters ovarian cancer spheroid formation and impacts peritoneal invasion
Lewis Francis
title_short Cisplatin resistance alters ovarian cancer spheroid formation and impacts peritoneal invasion
title_full Cisplatin resistance alters ovarian cancer spheroid formation and impacts peritoneal invasion
title_fullStr Cisplatin resistance alters ovarian cancer spheroid formation and impacts peritoneal invasion
title_full_unstemmed Cisplatin resistance alters ovarian cancer spheroid formation and impacts peritoneal invasion
title_sort Cisplatin resistance alters ovarian cancer spheroid formation and impacts peritoneal invasion
author_id_str_mv 10f61f9c1248951c1a33f6a89498f37d
author_id_fullname_str_mv 10f61f9c1248951c1a33f6a89498f37d_***_Lewis Francis
author Lewis Francis
author2 Lewis Francis
format Journal article
container_title Frontiers in Cell and Development Biology
institution Swansea University
doi_str_mv 10.3389/fcell.2025.1450407
publisher Frontiers
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 - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
document_store_str 0
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description Epithelial ovarian cancer (EOC) is an aggressive and lethal gynaecologic malignancy due to late diagnosis and acquired resistance to chemotherapeutic drugs, such as cisplatin. EOC metastasis commonly occurs through the extensive dissemination of multicellular aggregates, formed of cells originally shed from the primary ovarian tumour, within the peritoneal cavity.However, little is known about how cisplatin resistance (CR) alters the biophysical properties of EOC multicellular aggregates and how this impacts metastasis. In this interdisciplinary study, light and atomic force microscopy was used, alongside quantitative gene and protein expression analysis, to reveal distinct differences in the biophysical properties of CR spheroids, which correlated with altered protein expression of plasminogen activator inhibitor-1 (PAI-1) and Tenascin-C. CR SKOV3 spheroids (IC50: 25.5 µM) had a significantly greater area and perimeter and were less spherical, with a reduced Young's modulus, (p< 0.01) compared to parental (P) SKOV3 spheroids (IC50: 5.4 µM). Gene expression arrays revealed up-regulation of genes associated with cell adhesion, ECM and epithelial-to-mesenchymal transition (EMT) in CR spheroids, while immunofluorescence assays demonstrated increased protein expression of PAI-1 (p<0.05; implicated in cell adhesion) and reduced protein expression of Tenascin-C (p<0.01; implicated in elasticity) in CR spheroids compared to P spheroids. Furthermore, the CR spheroids demonstrated altered interactions with a surface that mimics the peritoneal liningsurface post mesothelial clearance (Matrigel). CR spheroids were significantly less adhesive with reduced disaggregation on Matrigel surfaces, compared to P spheroids (p<0.05), while CR cells were more invasive compared to P cells. The combined characterisation of the biophysical and biological roles of EOC multicellular aggregates in drug resistance and metastasis highlight key proteins which could be responsible for altered metastatic progression that may occur in patients that present with cisplatin resistance.
published_date 0001-01-01T05:49:43Z
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