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Adipocyte Derived Exosomes Promote Cell Invasion and Challenge Paclitaxel Efficacy in Ovarian Cancer

Michael Ellis Williams, David Howard, Claire Donnelly, Fereshteh Izadi, Jezabel Garcia Parra, Meg Pugh, KADIE EDWARDS, Kerryn Lutchman-Sigh, Sadie Jones, Lavinia Margarit, Lewis Francis Orcid Logo, Steve Conlan Orcid Logo, Francesca Taraballi, Deya Gonzalez Orcid Logo

Cell Communication and Signaling

Swansea University Authors: David Howard, Claire Donnelly, Jezabel Garcia Parra, Meg Pugh, KADIE EDWARDS, Lewis Francis Orcid Logo, Steve Conlan Orcid Logo, Deya Gonzalez Orcid Logo

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DOI (Published version): 10.1186/s12964-024-01806-4

Abstract

Background: Epithelial ovarian cancer (EOC) is the deadliest gynaecological cancer with high mortality rates driven by the common development of resistance to chemotherapy. EOC frequently invades the omentum, an adipocyte-rich organ of the peritoneum and omental adipocytes have been implicated in pr...

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Published in: Cell Communication and Signaling
Published: Springer 2024
URI: https://cronfa.swan.ac.uk/Record/cronfa67596
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EOC frequently invades the omentum, an adipocyte-rich organ of the peritoneum and omental adipocytes have been implicated in promoting disease progression, metastasis and chemoresistance. The signalling mechanisms underpinning EOC omentum tropism have yet to be elucidated. Methods: Three-dimensional co-culture models were used to explore adipocyte-EOC interactions. The impact of adipocytes on EOC proliferation, response to therapy and invasive capacity was assessed. Primary adipocytes and omental tissue were isolated from patients with ovarian malignancies and benign ovarian neoplasms. Exosomes were isolated from omentum tissue conditioned media and the effect of omentum-derived exosomes on EOC evaluated. Exosomal microRNA (miRNA) sequencing was used to identify miRNAs abundant in omental exosomes and EOC cells were transfected with highly abundant miRNAs miR-21, let-7b, miR-16 and miR-92a. Results: We demonstrate the capacity of adipocytes to induce an invasive phenotype in EOC populations through driving epithelial-to-mesenchymal transition (EMT). Exosomes secreted by omental tissue of ovarian cancer patients, as well as patients without malignancies, induced proliferation, upregulated EMT markers and reduced response to paclitaxel therapy in EOC cell lines and HGSOC patient samples. Analysis of the omentum-derived exosomes from cancer patients revealed highly abundant miRNAs that included miR-21, let-7b, miR-16 and miR-92a that promoted cancer cell proliferation and protection from chemotherapy when transfected in ovarian cancer cells.Conclusions: These observations highlight the capacity of omental adipocytes to generate a pro-tumorigenic and chemoprotective microenvironment in ovarian cancer and other adipose-related malignancies.</abstract><type>Journal Article</type><journal>Cell Communication and Signaling</journal><volume>0</volume><journalNumber/><paginationStart/><paginationEnd/><publisher>Springer</publisher><placeOfPublication/><isbnPrint/><isbnElectronic/><issnPrint/><issnElectronic/><keywords>Ovarian cancer, Omentum, Adipocytes, Exosomes, miRNA, Mir-21, Prolactin, Obesity</keywords><publishedDay>16</publishedDay><publishedMonth>9</publishedMonth><publishedYear>2024</publishedYear><publishedDate>2024-09-16</publishedDate><doi>10.1186/s12964-024-01806-4</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 Health Care Research Wales (HCRW) studentship grant HS-16-38, 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 grants (2017/COL/001 and 2017/COL/004), and Swansea University Texas academic partnership PhD programme.</funders><projectreference/><lastEdited>2024-09-18T12:40:18.1304297</lastEdited><Created>2024-09-05T14:09:01.1403088</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>Michael Ellis</firstname><surname>Williams</surname><order>1</order></author><author><firstname>David</firstname><surname>Howard</surname><order>2</order></author><author><firstname>Claire</firstname><surname>Donnelly</surname><order>3</order></author><author><firstname>Fereshteh</firstname><surname>Izadi</surname><order>4</order></author><author><firstname>Jezabel</firstname><surname>Garcia Parra</surname><order>5</order></author><author><firstname>Meg</firstname><surname>Pugh</surname><order>6</order></author><author><firstname>KADIE</firstname><surname>EDWARDS</surname><order>7</order></author><author><firstname>Kerryn</firstname><surname>Lutchman-Sigh</surname><order>8</order></author><author><firstname>Sadie</firstname><surname>Jones</surname><order>9</order></author><author><firstname>Lavinia</firstname><surname>Margarit</surname><order>10</order></author><author><firstname>Lewis</firstname><surname>Francis</surname><orcid>0000-0002-7803-7714</orcid><order>11</order></author><author><firstname>Steve</firstname><surname>Conlan</surname><orcid>0000-0002-2562-3461</orcid><order>12</order></author><author><firstname>Francesca</firstname><surname>Taraballi</surname><order>13</order></author><author><firstname>Deya</firstname><surname>Gonzalez</surname><orcid>0000-0002-1838-6752</orcid><order>14</order></author></authors><documents><document><filename>67596__31362__dbe8db98680244aba84e21464ec755a3.pdf</filename><originalFilename>67596.VOR.pdf</originalFilename><uploaded>2024-09-18T12:26:53.8897860</uploaded><type>Output</type><contentLength>6646825</contentLength><contentType>application/pdf</contentType><version>Version of Record</version><cronfaStatus>true</cronfaStatus><documentNotes>© The Author(s) 2024. 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spelling v2 67596 2024-09-05 Adipocyte Derived Exosomes Promote Cell Invasion and Challenge Paclitaxel Efficacy in Ovarian Cancer c7c303f6cb3c54c8f7ed2563c1a39759 David Howard David Howard true false a0d305c32324d1d1d1fb4520e80af724 Claire Donnelly Claire Donnelly true false f0342a6c8de90d52996ac44f44908f68 Jezabel Garcia Parra Jezabel Garcia Parra true false 7e08d7f5a7f94d6fc3e305959cb5957c Meg Pugh Meg Pugh true false 8544f42ce07a33e7297152c239f39864 KADIE EDWARDS KADIE EDWARDS true false 10f61f9c1248951c1a33f6a89498f37d 0000-0002-7803-7714 Lewis Francis Lewis Francis true false 0bb6bd247e32fb4249de62c0013b51cb 0000-0002-2562-3461 Steve Conlan Steve Conlan true false bafdf635eb81280304eedf4b18e65d4e 0000-0002-1838-6752 Deya Gonzalez Deya Gonzalez true false 2024-09-05 MEDS Background: Epithelial ovarian cancer (EOC) is the deadliest gynaecological cancer with high mortality rates driven by the common development of resistance to chemotherapy. EOC frequently invades the omentum, an adipocyte-rich organ of the peritoneum and omental adipocytes have been implicated in promoting disease progression, metastasis and chemoresistance. The signalling mechanisms underpinning EOC omentum tropism have yet to be elucidated. Methods: Three-dimensional co-culture models were used to explore adipocyte-EOC interactions. The impact of adipocytes on EOC proliferation, response to therapy and invasive capacity was assessed. Primary adipocytes and omental tissue were isolated from patients with ovarian malignancies and benign ovarian neoplasms. Exosomes were isolated from omentum tissue conditioned media and the effect of omentum-derived exosomes on EOC evaluated. Exosomal microRNA (miRNA) sequencing was used to identify miRNAs abundant in omental exosomes and EOC cells were transfected with highly abundant miRNAs miR-21, let-7b, miR-16 and miR-92a. Results: We demonstrate the capacity of adipocytes to induce an invasive phenotype in EOC populations through driving epithelial-to-mesenchymal transition (EMT). Exosomes secreted by omental tissue of ovarian cancer patients, as well as patients without malignancies, induced proliferation, upregulated EMT markers and reduced response to paclitaxel therapy in EOC cell lines and HGSOC patient samples. Analysis of the omentum-derived exosomes from cancer patients revealed highly abundant miRNAs that included miR-21, let-7b, miR-16 and miR-92a that promoted cancer cell proliferation and protection from chemotherapy when transfected in ovarian cancer cells.Conclusions: These observations highlight the capacity of omental adipocytes to generate a pro-tumorigenic and chemoprotective microenvironment in ovarian cancer and other adipose-related malignancies. Journal Article Cell Communication and Signaling 0 Springer Ovarian cancer, Omentum, Adipocytes, Exosomes, miRNA, Mir-21, Prolactin, Obesity 16 9 2024 2024-09-16 10.1186/s12964-024-01806-4 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 Health Care Research Wales (HCRW) studentship grant HS-16-38, 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 grants (2017/COL/001 and 2017/COL/004), and Swansea University Texas academic partnership PhD programme. 2024-09-18T12:40:18.1304297 2024-09-05T14:09:01.1403088 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Michael Ellis Williams 1 David Howard 2 Claire Donnelly 3 Fereshteh Izadi 4 Jezabel Garcia Parra 5 Meg Pugh 6 KADIE EDWARDS 7 Kerryn Lutchman-Sigh 8 Sadie Jones 9 Lavinia Margarit 10 Lewis Francis 0000-0002-7803-7714 11 Steve Conlan 0000-0002-2562-3461 12 Francesca Taraballi 13 Deya Gonzalez 0000-0002-1838-6752 14 67596__31362__dbe8db98680244aba84e21464ec755a3.pdf 67596.VOR.pdf 2024-09-18T12:26:53.8897860 Output 6646825 application/pdf Version of Record true © The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. true eng http://creativecommons.org/licenses/by/4.0/
title Adipocyte Derived Exosomes Promote Cell Invasion and Challenge Paclitaxel Efficacy in Ovarian Cancer
spellingShingle Adipocyte Derived Exosomes Promote Cell Invasion and Challenge Paclitaxel Efficacy in Ovarian Cancer
David Howard
Claire Donnelly
Jezabel Garcia Parra
Meg Pugh
KADIE EDWARDS
Lewis Francis
Steve Conlan
Deya Gonzalez
title_short Adipocyte Derived Exosomes Promote Cell Invasion and Challenge Paclitaxel Efficacy in Ovarian Cancer
title_full Adipocyte Derived Exosomes Promote Cell Invasion and Challenge Paclitaxel Efficacy in Ovarian Cancer
title_fullStr Adipocyte Derived Exosomes Promote Cell Invasion and Challenge Paclitaxel Efficacy in Ovarian Cancer
title_full_unstemmed Adipocyte Derived Exosomes Promote Cell Invasion and Challenge Paclitaxel Efficacy in Ovarian Cancer
title_sort Adipocyte Derived Exosomes Promote Cell Invasion and Challenge Paclitaxel Efficacy in Ovarian Cancer
author_id_str_mv c7c303f6cb3c54c8f7ed2563c1a39759
a0d305c32324d1d1d1fb4520e80af724
f0342a6c8de90d52996ac44f44908f68
7e08d7f5a7f94d6fc3e305959cb5957c
8544f42ce07a33e7297152c239f39864
10f61f9c1248951c1a33f6a89498f37d
0bb6bd247e32fb4249de62c0013b51cb
bafdf635eb81280304eedf4b18e65d4e
author_id_fullname_str_mv c7c303f6cb3c54c8f7ed2563c1a39759_***_David Howard
a0d305c32324d1d1d1fb4520e80af724_***_Claire Donnelly
f0342a6c8de90d52996ac44f44908f68_***_Jezabel Garcia Parra
7e08d7f5a7f94d6fc3e305959cb5957c_***_Meg Pugh
8544f42ce07a33e7297152c239f39864_***_KADIE EDWARDS
10f61f9c1248951c1a33f6a89498f37d_***_Lewis Francis
0bb6bd247e32fb4249de62c0013b51cb_***_Steve Conlan
bafdf635eb81280304eedf4b18e65d4e_***_Deya Gonzalez
author David Howard
Claire Donnelly
Jezabel Garcia Parra
Meg Pugh
KADIE EDWARDS
Lewis Francis
Steve Conlan
Deya Gonzalez
author2 Michael Ellis Williams
David Howard
Claire Donnelly
Fereshteh Izadi
Jezabel Garcia Parra
Meg Pugh
KADIE EDWARDS
Kerryn Lutchman-Sigh
Sadie Jones
Lavinia Margarit
Lewis Francis
Steve Conlan
Francesca Taraballi
Deya Gonzalez
format Journal article
container_title Cell Communication and Signaling
container_volume 0
publishDate 2024
institution Swansea University
doi_str_mv 10.1186/s12964-024-01806-4
publisher Springer
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 1
active_str 0
description Background: Epithelial ovarian cancer (EOC) is the deadliest gynaecological cancer with high mortality rates driven by the common development of resistance to chemotherapy. EOC frequently invades the omentum, an adipocyte-rich organ of the peritoneum and omental adipocytes have been implicated in promoting disease progression, metastasis and chemoresistance. The signalling mechanisms underpinning EOC omentum tropism have yet to be elucidated. Methods: Three-dimensional co-culture models were used to explore adipocyte-EOC interactions. The impact of adipocytes on EOC proliferation, response to therapy and invasive capacity was assessed. Primary adipocytes and omental tissue were isolated from patients with ovarian malignancies and benign ovarian neoplasms. Exosomes were isolated from omentum tissue conditioned media and the effect of omentum-derived exosomes on EOC evaluated. Exosomal microRNA (miRNA) sequencing was used to identify miRNAs abundant in omental exosomes and EOC cells were transfected with highly abundant miRNAs miR-21, let-7b, miR-16 and miR-92a. Results: We demonstrate the capacity of adipocytes to induce an invasive phenotype in EOC populations through driving epithelial-to-mesenchymal transition (EMT). Exosomes secreted by omental tissue of ovarian cancer patients, as well as patients without malignancies, induced proliferation, upregulated EMT markers and reduced response to paclitaxel therapy in EOC cell lines and HGSOC patient samples. Analysis of the omentum-derived exosomes from cancer patients revealed highly abundant miRNAs that included miR-21, let-7b, miR-16 and miR-92a that promoted cancer cell proliferation and protection from chemotherapy when transfected in ovarian cancer cells.Conclusions: These observations highlight the capacity of omental adipocytes to generate a pro-tumorigenic and chemoprotective microenvironment in ovarian cancer and other adipose-related malignancies.
published_date 2024-09-16T12:40:17Z
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score 11.028798

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