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Cisplatin resistance alters ovarian cancer spheroid formation and impacts peritoneal invasion
Lydia Powell 
,
Marcos Quintela Vazquez,
David James,
Emenike Onyido,
David Howard,
Kadie Edwards ,
Jordan Turney,
Charlotte Morgan,
Jenny Worthington,
Nicole Williams,
Alexander Dulebo,
Heiko Haschke,
Deya Gonzalez ,
Steve Conlan ,
Lewis Francis
,
Marcos Quintela Vazquez,
David James,
Emenike Onyido,
David Howard,
Kadie Edwards ,
Jordan Turney,
Charlotte Morgan,
Jenny Worthington,
Nicole Williams,
Alexander Dulebo,
Heiko Haschke,
Deya Gonzalez ,
Steve Conlan ,
Lewis Francis
Frontiers in Cell and Developmental Biology, Volume: 13, Start page: 1450407
Swansea University Authors:
Lydia Powell , Marcos Quintela Vazquez, David James, Emenike Onyido, David Howard, Kadie Edwards , Jordan Turney, Charlotte Morgan, Deya Gonzalez , Steve Conlan , Lewis Francis
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© 2025 Powell, Quintela, James, Onyido, Howard, Edwards, Turney, Morgan, Worthington, Williams, Dulebo, Haschke, Gonzalez, Conlan and Francis. This is an openaccess article distributed under the terms of the Creative Commons Attribution License (CC BY).
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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...
| Published in: | Frontiers in Cell and Developmental Biology |
|---|---|
| ISSN: | 2296-634X |
| Published: |
Frontiers Media SA
2025
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| URI: | https://cronfa.swan.ac.uk/Record/cronfa68707 |
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2025-01-17T13:35:10Z |
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2025-02-19T07:28:38Z |
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<?xml version="1.0"?><rfc1807><datestamp>2025-02-18T12:55:35.4085080</datestamp><bib-version>v2</bib-version><id>68707</id><entry>2025-01-17</entry><title>Cisplatin resistance alters ovarian cancer spheroid formation and impacts peritoneal invasion</title><swanseaauthors><author><sid>0e7e702952672bcbfdfd4974199202fb</sid><ORCID>0000-0002-8641-0160</ORCID><firstname>Lydia</firstname><surname>Powell</surname><name>Lydia Powell</name><active>true</active><ethesisStudent>false</ethesisStudent></author><author><sid>29d006fa16d293ca29762fce9c356f8e</sid><firstname>Marcos</firstname><surname>Quintela Vazquez</surname><name>Marcos Quintela Vazquez</name><active>true</active><ethesisStudent>false</ethesisStudent></author><author><sid>31b39419835be9525450cf1420e63996</sid><firstname>David</firstname><surname>James</surname><name>David James</name><active>true</active><ethesisStudent>false</ethesisStudent></author><author><sid>ced59d5f3e43ba56ad013792bea973a0</sid><firstname>Emenike</firstname><surname>Onyido</surname><name>Emenike Onyido</name><active>true</active><ethesisStudent>false</ethesisStudent></author><author><sid>c7c303f6cb3c54c8f7ed2563c1a39759</sid><firstname>David</firstname><surname>Howard</surname><name>David Howard</name><active>true</active><ethesisStudent>false</ethesisStudent></author><author><sid>76d053c090d5064ae9558888f7985e92</sid><ORCID>0000-0002-1359-0359</ORCID><firstname>Kadie</firstname><surname>Edwards</surname><name>Kadie Edwards</name><active>true</active><ethesisStudent>false</ethesisStudent></author><author><sid>00b45d9efb571c2755abdc33b4d828a9</sid><firstname>Jordan</firstname><surname>Turney</surname><name>Jordan Turney</name><active>true</active><ethesisStudent>false</ethesisStudent></author><author><sid>0355aeb12879661ec0184695d0da1df2</sid><firstname>Charlotte</firstname><surname>Morgan</surname><name>Charlotte Morgan</name><active>true</active><ethesisStudent>false</ethesisStudent></author><author><sid>bafdf635eb81280304eedf4b18e65d4e</sid><ORCID>0000-0002-1838-6752</ORCID><firstname>Deya</firstname><surname>Gonzalez</surname><name>Deya Gonzalez</name><active>true</active><ethesisStudent>false</ethesisStudent></author><author><sid>0bb6bd247e32fb4249de62c0013b51cb</sid><ORCID>0000-0002-2562-3461</ORCID><firstname>Steve</firstname><surname>Conlan</surname><name>Steve Conlan</name><active>true</active><ethesisStudent>false</ethesisStudent></author><author><sid>10f61f9c1248951c1a33f6a89498f37d</sid><ORCID>0000-0002-7803-7714</ORCID><firstname>Lewis</firstname><surname>Francis</surname><name>Lewis Francis</name><active>true</active><ethesisStudent>false</ethesisStudent></author></swanseaauthors><date>2025-01-17</date><deptcode>MEDS</deptcode><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 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.</abstract><type>Journal Article</type><journal>Frontiers in Cell and Developmental Biology</journal><volume>13</volume><journalNumber/><paginationStart>1450407</paginationStart><paginationEnd/><publisher>Frontiers Media SA</publisher><placeOfPublication/><isbnPrint/><isbnElectronic/><issnPrint/><issnElectronic>2296-634X</issnElectronic><keywords>ovarian cancer, spheroids, biophysics, invasion, atomic force microscopy, cisplatin</keywords><publishedDay>5</publishedDay><publishedMonth>2</publishedMonth><publishedYear>2025</publishedYear><publishedDate>2025-02-05</publishedDate><doi>10.3389/fcell.2025.1450407</doi><url/><notes/><college>COLLEGE NANME</college><department>Medical School</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>MEDS</DepartmentCode><institution>Swansea University</institution><apcterm>External research funder(s) paid the OA fee (includes OA grants disbursed by the Library)</apcterm><funders>The project was funded by the Medical Research Council UK Confidence in Concept grant (MC_PC_19053), the Medical Research Council UK Impact Acceleration Account grant (MR/X502686/1), Welsh Government ERDF SMART Expertise 2014–2022 West Wales and the Valleys grant (2017/COL/004).</funders><projectreference/><lastEdited>2025-02-18T12:55:35.4085080</lastEdited><Created>2025-01-17T13:33:19.3937186</Created><path><level id="1">Faculty of Medicine, Health and Life Sciences</level><level id="2">Swansea University Medical School - Medicine</level></path><authors><author><firstname>Lydia</firstname><surname>Powell</surname><orcid>0000-0002-8641-0160</orcid><order>1</order></author><author><firstname>Marcos</firstname><surname>Quintela Vazquez</surname><order>2</order></author><author><firstname>David</firstname><surname>James</surname><order>3</order></author><author><firstname>Emenike</firstname><surname>Onyido</surname><order>4</order></author><author><firstname>David</firstname><surname>Howard</surname><order>5</order></author><author><firstname>Kadie</firstname><surname>Edwards</surname><orcid>0000-0002-1359-0359</orcid><order>6</order></author><author><firstname>Jordan</firstname><surname>Turney</surname><order>7</order></author><author><firstname>Charlotte</firstname><surname>Morgan</surname><order>8</order></author><author><firstname>Jenny</firstname><surname>Worthington</surname><order>9</order></author><author><firstname>Nicole</firstname><surname>Williams</surname><order>10</order></author><author><firstname>Alexander</firstname><surname>Dulebo</surname><order>11</order></author><author><firstname>Heiko</firstname><surname>Haschke</surname><order>12</order></author><author><firstname>Deya</firstname><surname>Gonzalez</surname><orcid>0000-0002-1838-6752</orcid><order>13</order></author><author><firstname>Steve</firstname><surname>Conlan</surname><orcid>0000-0002-2562-3461</orcid><order>14</order></author><author><firstname>Lewis</firstname><surname>Francis</surname><orcid>0000-0002-7803-7714</orcid><order>15</order></author></authors><documents><document><filename>68707__33626__cb56171c0a6a429aa2763903e4213849.pdf</filename><originalFilename>68707.VOR.pdf</originalFilename><uploaded>2025-02-18T12:51:54.3035662</uploaded><type>Output</type><contentLength>2540733</contentLength><contentType>application/pdf</contentType><version>Version of Record</version><cronfaStatus>true</cronfaStatus><documentNotes>© 2025 Powell, Quintela, James, Onyido, Howard, Edwards, Turney, Morgan, Worthington, Williams, Dulebo, Haschke, Gonzalez, Conlan and Francis. 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2025-02-18T12:55:35.4085080 v2 68707 2025-01-17 Cisplatin resistance alters ovarian cancer spheroid formation and impacts peritoneal invasion 0e7e702952672bcbfdfd4974199202fb 0000-0002-8641-0160 Lydia Powell Lydia Powell true false 29d006fa16d293ca29762fce9c356f8e Marcos Quintela Vazquez Marcos Quintela Vazquez true false 31b39419835be9525450cf1420e63996 David James David James true false ced59d5f3e43ba56ad013792bea973a0 Emenike Onyido Emenike Onyido true false c7c303f6cb3c54c8f7ed2563c1a39759 David Howard David Howard true false 76d053c090d5064ae9558888f7985e92 0000-0002-1359-0359 Kadie Edwards Kadie Edwards true false 00b45d9efb571c2755abdc33b4d828a9 Jordan Turney Jordan Turney true false 0355aeb12879661ec0184695d0da1df2 Charlotte Morgan Charlotte Morgan true false bafdf635eb81280304eedf4b18e65d4e 0000-0002-1838-6752 Deya Gonzalez Deya Gonzalez true false 0bb6bd247e32fb4249de62c0013b51cb 0000-0002-2562-3461 Steve Conlan Steve Conlan true false 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 Developmental Biology 13 1450407 Frontiers Media SA 2296-634X ovarian cancer, spheroids, biophysics, invasion, atomic force microscopy, cisplatin 5 2 2025 2025-02-05 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) The project was funded by the Medical Research Council UK Confidence in Concept grant (MC_PC_19053), the Medical Research Council UK Impact Acceleration Account grant (MR/X502686/1), Welsh Government ERDF SMART Expertise 2014–2022 West Wales and the Valleys grant (2017/COL/004). 2025-02-18T12:55:35.4085080 2025-01-17T13:33:19.3937186 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Lydia Powell 0000-0002-8641-0160 1 Marcos Quintela Vazquez 2 David James 3 Emenike Onyido 4 David Howard 5 Kadie Edwards 0000-0002-1359-0359 6 Jordan Turney 7 Charlotte Morgan 8 Jenny Worthington 9 Nicole Williams 10 Alexander Dulebo 11 Heiko Haschke 12 Deya Gonzalez 0000-0002-1838-6752 13 Steve Conlan 0000-0002-2562-3461 14 Lewis Francis 0000-0002-7803-7714 15 68707__33626__cb56171c0a6a429aa2763903e4213849.pdf 68707.VOR.pdf 2025-02-18T12:51:54.3035662 Output 2540733 application/pdf Version of Record true © 2025 Powell, Quintela, James, Onyido, Howard, Edwards, Turney, Morgan, Worthington, Williams, Dulebo, Haschke, Gonzalez, Conlan and Francis. This is an openaccess article distributed under the terms of the Creative Commons Attribution License (CC BY). true eng https://creativecommons.org/licenses/by/4.0/ |
| title |
Cisplatin resistance alters ovarian cancer spheroid formation and impacts peritoneal invasion |
| spellingShingle |
Cisplatin resistance alters ovarian cancer spheroid formation and impacts peritoneal invasion Lydia Powell Marcos Quintela Vazquez David James Emenike Onyido David Howard Kadie Edwards Jordan Turney Charlotte Morgan Deya Gonzalez Steve Conlan 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 |
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Lydia Powell Marcos Quintela Vazquez David James Emenike Onyido David Howard Kadie Edwards Jordan Turney Charlotte Morgan Deya Gonzalez Steve Conlan Lewis Francis |
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Lydia Powell Marcos Quintela Vazquez David James Emenike Onyido David Howard Kadie Edwards Jordan Turney Charlotte Morgan Jenny Worthington Nicole Williams Alexander Dulebo Heiko Haschke Deya Gonzalez Steve Conlan Lewis Francis |
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Frontiers Media SA |
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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. |
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2025-02-05T08:30:38Z |
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