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Unlocking the diagnostic power of plasma extracellular vesicle miR-200 family in pancreatic ductal adenocarcinoma

Daniel S.K. Liu, Jisce R. Puik, Bhavik Y. Patel, Morten T. Venø, Mahrou Vahabi, Mireia Mato Prado, Jason Webber Orcid Logo, Eleanor Rees, Flora M. Upton, Kate Bennett, Catherine Blaker, Benoit Immordino, Annalisa Comandatore, Luca Morelli, Shivan Sivakumar, Rutger-Jan Swijnenburg, Marc G. Besselink, Long R. Jiao, Geert Kazemier, Elisa Giovannetti Orcid Logo, Jonathan Krell, Adam E. Frampton

Journal of Experimental & Clinical Cancer Research, Volume: 43, Issue: 1

Swansea University Author: Jason Webber Orcid Logo

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DOI (Published version): 10.1186/s13046-024-03090-z

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BackgroundDistinguishing benign from malignant pancreaticobiliary disease is challenging because of the absence of reliable biomarkers. Circulating extracellular vesicles (EVs) have emerged as functional mediators between cells. Their cargos, including microRNAs (miRNAs), are increasingly acknowledg...

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Published in: Journal of Experimental & Clinical Cancer Research
ISSN: 1756-9966
Published: Springer Science and Business Media LLC 2024
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Their cargos, including microRNAs (miRNAs), are increasingly acknowledged as an important source of potential biomarkers. This multicentric, prospective study aimed to establish a diagnostic plasma EV-derived miRNA signature to discriminate pancreatic ductal adenocarcinoma (PDAC) from benign pancreaticobiliary disease.MethodsPlasma EVs were isolated using size exclusion chromatography (SEC) and characterised using nanoparticle tracking analysis, electron microscopy and Western blotting. EV-RNAs underwent small RNA sequencing to discover differentially expressed markers for PDAC (n = 10 benign vs. 10 PDAC). Candidate EV-miRNAs were then validated in a cohort of 61 patients (n = 31 benign vs. 30 PDAC) by RT-qPCR. Logistic regression and optimal thresholds (Youden Index) were used to develop an EV-miR-200 family model to detect cancer. This model was tested in an independent cohort of 95 patients (n = 30 benign, 33 PDAC, and 32 cholangiocarcinoma).ResultsSmall RNA sequencing and RT-qPCR showed that EV-miR-200 family members were significantly overexpressed in PDAC vs. benign disease. Combined expression of the EV-miR-200 family showed an AUC of 0.823. In an independent validation cohort, application of this model showed a sensitivity, specificity and AUC of 100%, 88%, and 0.97, respectively, for diagnosing PDAC.ConclusionsThis is the first study to validate plasma EV-miR-200 members as a clinically-useful diagnostic biomarker for PDAC. Further validation in larger cohorts and clinical trials is essential. These findings also suggest the potential utility in monitoring response and/or recurrence.</abstract><type>Journal Article</type><journal>Journal of Experimental &amp;amp; Clinical Cancer Research</journal><volume>43</volume><journalNumber>1</journalNumber><paginationStart/><paginationEnd/><publisher>Springer Science and Business Media LLC</publisher><placeOfPublication/><isbnPrint/><isbnElectronic/><issnPrint/><issnElectronic>1756-9966</issnElectronic><keywords>Biomarkers; Extracellular vesicles; Pancreatic ductal adenocarcinoma; microRNAs.</keywords><publishedDay>8</publishedDay><publishedMonth>7</publishedMonth><publishedYear>2024</publishedYear><publishedDate>2024-07-08</publishedDate><doi>10.1186/s13046-024-03090-z</doi><url/><notes/><college>COLLEGE NANME</college><department>Medical School</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>MEDS</DepartmentCode><institution>Swansea University</institution><apcterm>Another institution paid the OA fee</apcterm><funders>This research was funded by The Jon Moulton Charity Trust, UK (AEF); Action Against Cancer, UK (DKSL, MMP, ER, BP, LRJ, JK, AEF); the Royal College of Surgeons of Edinburgh, UK (AEF); the Royal College of Surgeons of England (AEF, DSKL); the Mason Medical Research Foundation, UK (AEF); the S.A.L. Charitable Fund, UK (AEF); BRIGHT cancer charity (AEF, BYP); the Bennink Foundation, the Netherlands (JRP, GK, EG); Italian Association for Cancer Research AIRC, Italy (EG); PANOMIC grant by Fondazione Pisa (AC, LM, EG); Fondazione Pisana Per La Scienza, Italy (EG); and the Dutch Cancer Society KWF (RJS, EG, GK).</funders><projectreference/><lastEdited>2024-08-30T15:24:04.1547321</lastEdited><Created>2024-07-09T15:47:16.4840799</Created><path><level id="1">Faculty of Medicine, Health and Life Sciences</level><level id="2">Swansea University Medical School - Biomedical Science</level></path><authors><author><firstname>Daniel S.K.</firstname><surname>Liu</surname><order>1</order></author><author><firstname>Jisce R.</firstname><surname>Puik</surname><order>2</order></author><author><firstname>Bhavik Y.</firstname><surname>Patel</surname><order>3</order></author><author><firstname>Morten T.</firstname><surname>Venø</surname><order>4</order></author><author><firstname>Mahrou</firstname><surname>Vahabi</surname><order>5</order></author><author><firstname>Mireia Mato</firstname><surname>Prado</surname><order>6</order></author><author><firstname>Jason</firstname><surname>Webber</surname><orcid>0000-0003-4772-3014</orcid><order>7</order></author><author><firstname>Eleanor</firstname><surname>Rees</surname><order>8</order></author><author><firstname>Flora M.</firstname><surname>Upton</surname><order>9</order></author><author><firstname>Kate</firstname><surname>Bennett</surname><order>10</order></author><author><firstname>Catherine</firstname><surname>Blaker</surname><order>11</order></author><author><firstname>Benoit</firstname><surname>Immordino</surname><order>12</order></author><author><firstname>Annalisa</firstname><surname>Comandatore</surname><order>13</order></author><author><firstname>Luca</firstname><surname>Morelli</surname><order>14</order></author><author><firstname>Shivan</firstname><surname>Sivakumar</surname><order>15</order></author><author><firstname>Rutger-Jan</firstname><surname>Swijnenburg</surname><order>16</order></author><author><firstname>Marc G.</firstname><surname>Besselink</surname><order>17</order></author><author><firstname>Long R.</firstname><surname>Jiao</surname><order>18</order></author><author><firstname>Geert</firstname><surname>Kazemier</surname><order>19</order></author><author><firstname>Elisa</firstname><surname>Giovannetti</surname><orcid>0000-0002-7565-7504</orcid><order>20</order></author><author><firstname>Jonathan</firstname><surname>Krell</surname><order>21</order></author><author><firstname>Adam E.</firstname><surname>Frampton</surname><order>22</order></author></authors><documents><document><filename>67056__31199__2eee4acacbce454d96730d6a0573eedf.pdf</filename><originalFilename>67056.VoR.pdf</originalFilename><uploaded>2024-08-30T15:15:06.8587206</uploaded><type>Output</type><contentLength>3938218</contentLength><contentType>application/pdf</contentType><version>Version of Record</version><cronfaStatus>true</cronfaStatus><documentNotes>© The Author(s) 2024. 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spelling v2 67056 2024-07-09 Unlocking the diagnostic power of plasma extracellular vesicle miR-200 family in pancreatic ductal adenocarcinoma 25d1a26f9b8bb556bd9412080e40351d 0000-0003-4772-3014 Jason Webber Jason Webber true false 2024-07-09 MEDS BackgroundDistinguishing benign from malignant pancreaticobiliary disease is challenging because of the absence of reliable biomarkers. Circulating extracellular vesicles (EVs) have emerged as functional mediators between cells. Their cargos, including microRNAs (miRNAs), are increasingly acknowledged as an important source of potential biomarkers. This multicentric, prospective study aimed to establish a diagnostic plasma EV-derived miRNA signature to discriminate pancreatic ductal adenocarcinoma (PDAC) from benign pancreaticobiliary disease.MethodsPlasma EVs were isolated using size exclusion chromatography (SEC) and characterised using nanoparticle tracking analysis, electron microscopy and Western blotting. EV-RNAs underwent small RNA sequencing to discover differentially expressed markers for PDAC (n = 10 benign vs. 10 PDAC). Candidate EV-miRNAs were then validated in a cohort of 61 patients (n = 31 benign vs. 30 PDAC) by RT-qPCR. Logistic regression and optimal thresholds (Youden Index) were used to develop an EV-miR-200 family model to detect cancer. This model was tested in an independent cohort of 95 patients (n = 30 benign, 33 PDAC, and 32 cholangiocarcinoma).ResultsSmall RNA sequencing and RT-qPCR showed that EV-miR-200 family members were significantly overexpressed in PDAC vs. benign disease. Combined expression of the EV-miR-200 family showed an AUC of 0.823. In an independent validation cohort, application of this model showed a sensitivity, specificity and AUC of 100%, 88%, and 0.97, respectively, for diagnosing PDAC.ConclusionsThis is the first study to validate plasma EV-miR-200 members as a clinically-useful diagnostic biomarker for PDAC. Further validation in larger cohorts and clinical trials is essential. These findings also suggest the potential utility in monitoring response and/or recurrence. Journal Article Journal of Experimental &amp; Clinical Cancer Research 43 1 Springer Science and Business Media LLC 1756-9966 Biomarkers; Extracellular vesicles; Pancreatic ductal adenocarcinoma; microRNAs. 8 7 2024 2024-07-08 10.1186/s13046-024-03090-z COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University Another institution paid the OA fee This research was funded by The Jon Moulton Charity Trust, UK (AEF); Action Against Cancer, UK (DKSL, MMP, ER, BP, LRJ, JK, AEF); the Royal College of Surgeons of Edinburgh, UK (AEF); the Royal College of Surgeons of England (AEF, DSKL); the Mason Medical Research Foundation, UK (AEF); the S.A.L. Charitable Fund, UK (AEF); BRIGHT cancer charity (AEF, BYP); the Bennink Foundation, the Netherlands (JRP, GK, EG); Italian Association for Cancer Research AIRC, Italy (EG); PANOMIC grant by Fondazione Pisa (AC, LM, EG); Fondazione Pisana Per La Scienza, Italy (EG); and the Dutch Cancer Society KWF (RJS, EG, GK). 2024-08-30T15:24:04.1547321 2024-07-09T15:47:16.4840799 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science Daniel S.K. Liu 1 Jisce R. Puik 2 Bhavik Y. Patel 3 Morten T. Venø 4 Mahrou Vahabi 5 Mireia Mato Prado 6 Jason Webber 0000-0003-4772-3014 7 Eleanor Rees 8 Flora M. Upton 9 Kate Bennett 10 Catherine Blaker 11 Benoit Immordino 12 Annalisa Comandatore 13 Luca Morelli 14 Shivan Sivakumar 15 Rutger-Jan Swijnenburg 16 Marc G. Besselink 17 Long R. Jiao 18 Geert Kazemier 19 Elisa Giovannetti 0000-0002-7565-7504 20 Jonathan Krell 21 Adam E. Frampton 22 67056__31199__2eee4acacbce454d96730d6a0573eedf.pdf 67056.VoR.pdf 2024-08-30T15:15:06.8587206 Output 3938218 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. true eng http://creativecommons.org/licenses/by/4.0/
title Unlocking the diagnostic power of plasma extracellular vesicle miR-200 family in pancreatic ductal adenocarcinoma
spellingShingle Unlocking the diagnostic power of plasma extracellular vesicle miR-200 family in pancreatic ductal adenocarcinoma
Jason Webber
title_short Unlocking the diagnostic power of plasma extracellular vesicle miR-200 family in pancreatic ductal adenocarcinoma
title_full Unlocking the diagnostic power of plasma extracellular vesicle miR-200 family in pancreatic ductal adenocarcinoma
title_fullStr Unlocking the diagnostic power of plasma extracellular vesicle miR-200 family in pancreatic ductal adenocarcinoma
title_full_unstemmed Unlocking the diagnostic power of plasma extracellular vesicle miR-200 family in pancreatic ductal adenocarcinoma
title_sort Unlocking the diagnostic power of plasma extracellular vesicle miR-200 family in pancreatic ductal adenocarcinoma
author_id_str_mv 25d1a26f9b8bb556bd9412080e40351d
author_id_fullname_str_mv 25d1a26f9b8bb556bd9412080e40351d_***_Jason Webber
author Jason Webber
author2 Daniel S.K. Liu
Jisce R. Puik
Bhavik Y. Patel
Morten T. Venø
Mahrou Vahabi
Mireia Mato Prado
Jason Webber
Eleanor Rees
Flora M. Upton
Kate Bennett
Catherine Blaker
Benoit Immordino
Annalisa Comandatore
Luca Morelli
Shivan Sivakumar
Rutger-Jan Swijnenburg
Marc G. Besselink
Long R. Jiao
Geert Kazemier
Elisa Giovannetti
Jonathan Krell
Adam E. Frampton
format Journal article
container_title Journal of Experimental &amp; Clinical Cancer Research
container_volume 43
container_issue 1
publishDate 2024
institution Swansea University
issn 1756-9966
doi_str_mv 10.1186/s13046-024-03090-z
publisher Springer Science and Business Media LLC
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 BackgroundDistinguishing benign from malignant pancreaticobiliary disease is challenging because of the absence of reliable biomarkers. Circulating extracellular vesicles (EVs) have emerged as functional mediators between cells. Their cargos, including microRNAs (miRNAs), are increasingly acknowledged as an important source of potential biomarkers. This multicentric, prospective study aimed to establish a diagnostic plasma EV-derived miRNA signature to discriminate pancreatic ductal adenocarcinoma (PDAC) from benign pancreaticobiliary disease.MethodsPlasma EVs were isolated using size exclusion chromatography (SEC) and characterised using nanoparticle tracking analysis, electron microscopy and Western blotting. EV-RNAs underwent small RNA sequencing to discover differentially expressed markers for PDAC (n = 10 benign vs. 10 PDAC). Candidate EV-miRNAs were then validated in a cohort of 61 patients (n = 31 benign vs. 30 PDAC) by RT-qPCR. Logistic regression and optimal thresholds (Youden Index) were used to develop an EV-miR-200 family model to detect cancer. This model was tested in an independent cohort of 95 patients (n = 30 benign, 33 PDAC, and 32 cholangiocarcinoma).ResultsSmall RNA sequencing and RT-qPCR showed that EV-miR-200 family members were significantly overexpressed in PDAC vs. benign disease. Combined expression of the EV-miR-200 family showed an AUC of 0.823. In an independent validation cohort, application of this model showed a sensitivity, specificity and AUC of 100%, 88%, and 0.97, respectively, for diagnosing PDAC.ConclusionsThis is the first study to validate plasma EV-miR-200 members as a clinically-useful diagnostic biomarker for PDAC. Further validation in larger cohorts and clinical trials is essential. These findings also suggest the potential utility in monitoring response and/or recurrence.
published_date 2024-07-08T15:24:03Z
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