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Extracellular vesicles from pancreatic cancer stem cells lead an intratumor communication network (EVNet) to fuel tumour progression

2022Artigo científico Acesso aberto
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dc.contributor.authorRuivo, Carolina F.
dc.contributor.authorBastos, Nuno
dc.contributor.authorAdem, Barbara
dc.contributor.authorBatista, Ines
dc.contributor.authorDuraes, Cecilia
dc.contributor.authorMelo, Carlos A.
dc.contributor.authorCastaldo, Stephanie A.
dc.contributor.authorCampos‐Laborie, Francisco
dc.contributor.authorMoutinho-Ribeiro, Pedro
dc.contributor.authorMorão, Barbara
dc.contributor.authorCosta-Pinto, Ana
dc.contributor.authorSilva, Soraia
dc.contributor.authorOsorio, Hugo
dc.contributor.authorCiordia, Sergio
dc.contributor.authorCosta, Jose Luis
dc.contributor.authorGoodrich, David
dc.contributor.authorCavadas, Bruno
dc.contributor.authorPereira, Luisa
dc.contributor.authorKouzarides, Tony
dc.contributor.authorMacedo, Guilherme
dc.contributor.authorMaio, Rui
dc.contributor.authorCarneiro, Fatima
dc.contributor.authorCravo, Marília
dc.contributor.authorKalluri, Raghu
dc.contributor.authorMachado, Jose Carlos
dc.contributor.authorMelo, Sonia A.
dc.date.accessioned2022-05-19T14:49:32Z
dc.date.available2022-05-19T14:49:32Z
dc.date.issued2022
dc.description© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. http://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.pt_PT
dc.description.abstractObjective: Intratumor heterogeneity drives cancer progression and therapy resistance. However, it has yet to be determined whether and how subpopulations of cancer cells interact and how this interaction affects the tumour. Design: We have studied the spontaneous flow of extracellular vesicles (EVs) between subpopulations of cancer cells: cancer stem cells (CSC) and non-stem cancer cells (NSCC). To determine the biological significance of the most frequent communication route, we used pancreatic ductal adenocarcinoma (PDAC) orthotopic models, patient-derived xenografts (PDXs) and genetically engineered mouse models (GEMMs). Results: We demonstrate that PDAC tumours establish an organised communication network between subpopulations of cancer cells using EVs called the EVNet). The EVNet is plastic and reshapes in response to its environment. Communication within the EVNet occurs preferentially from CSC to NSCC. Inhibition of this communication route by impairing Rab27a function in orthotopic xenographs, GEMMs and PDXs is sufficient to hamper tumour growth and phenocopies the inhibition of communication in the whole tumour. Mechanistically, we provide evidence that CSC EVs use agrin protein to promote Yes1 associated transcriptional regulator (YAP) activation via LDL receptor related protein 4 (LRP-4). Ex vivo treatment of PDXs with antiagrin significantly impairs proliferation and decreases the levels of activated YAP.Patients with high levels of agrin and low inactive YAP show worse disease-free survival. In addition, patients with a higher number of circulating agrin+ EVs show a significant increased risk of disease progression. Conclusion: PDAC tumours establish a cooperation network mediated by EVs that is led by CSC and agrin, which allows tumours to adapt and thrive. Targeting agrin could make targeted therapy possible for patients with PDAC and has a significant impact on CSC that feeds the tumour and is at the centre of therapy resistance.pt_PT
dc.description.sponsorshipThe work was supported by NORTE-01–0145-FEDER-000029, Norte Portugal Regional Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund and national funds through FCT—Foundation for Science and Technology POCI-01–0145-FEDER-32189. Programa Operacional Regional do Norte and co-financed by European Regional Development Fund under the project "The Porto Comprehensive Cancer Center" with the reference NORTE-01-0145-FEDER-072678 - Consórcio PORTO.CCC – Porto.Comprehensive Cancer Center. CFR is supported by FCT (SFRH/BD/131461/2017), NB by (SFRH/BD/130801/2017), IB by FCT (SFRH/BD/144854/2019), and BA by FCT (PD/BD/135546/2018). DG’s contribution was supported by the NCI (R21 CA179907). We acknowledge the support of the i3S Scientific Platforms: Translational Cytometry, Animal Facility, Bioimaging and Histology and Electron Microscopy are members of the national infrastructure PPBI - Portuguese Platform of Bioimaging (PPBI-POCI-01–0145-FEDER-022122). Proteomics was performed at the Proteomics Facility of The Spanish National Center for Biotechnology (CNB-CSIC), ProteoRed, PRB3-ISCIII, supported by grant PT17/0019.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationGut. 2022 Jan 10;gutjnl-2021-324994pt_PT
dc.identifier.doi10.1136/gutjnl-2021-324994pt_PT
dc.identifier.eissn1468-3288
dc.identifier.issn0017-5749
dc.identifier.urihttp://hdl.handle.net/10451/53076
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherBMJ Publishing Group Ltd.pt_PT
dc.relationNORTE-01–0145-FEDER-000029pt_PT
dc.relationPOCI-01–0145-FEDER-32189pt_PT
dc.relationNORTE-01-0145-FEDER-072678pt_PT
dc.relationPancExoNet: The role of exosomes-mediated communication in pancreatic cancer progression
dc.relationExoCanCell: The impact of exosomes biogenesis impairment in pancreatic cancer progression and therapy response
dc.relationNovo: Deconstructing the Immune Response in PDAC progression. Incicial: SHUSH CANCER CELLS – IMMUNOTHERAPY becoming a reality for PDAC PATIENTS
dc.relationExoBow: The Spatiotemporal biodistribution of pancreatic cancer exosomes
dc.relation.publisherversionhttps://gut.bmj.com/pt_PT
dc.rights.urihttp://creativecommons.org/licenses/by-nc/4.0/pt_PT
dc.subjectCarcinogenesispt_PT
dc.subjectCell biologypt_PT
dc.subjectMolecular carcinogenesispt_PT
dc.subjectPancreatic cancerpt_PT
dc.titleExtracellular vesicles from pancreatic cancer stem cells lead an intratumor communication network (EVNet) to fuel tumour progressionpt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardNumberSFRH/BD/131461/2017
oaire.awardNumberSFRH/BD/130801/2017
oaire.awardNumberSFRH/BD/144854/2019
oaire.awardNumberPD/BD/135546/2018
oaire.awardTitlePancExoNet: The role of exosomes-mediated communication in pancreatic cancer progression
oaire.awardTitleExoCanCell: The impact of exosomes biogenesis impairment in pancreatic cancer progression and therapy response
oaire.awardTitleNovo: Deconstructing the Immune Response in PDAC progression. Incicial: SHUSH CANCER CELLS – IMMUNOTHERAPY becoming a reality for PDAC PATIENTS
oaire.awardTitleExoBow: The Spatiotemporal biodistribution of pancreatic cancer exosomes
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//SFRH%2FBD%2F131461%2F2017/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/POR_NORTE/SFRH%2FBD%2F130801%2F2017/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/POR_NORTE/SFRH%2FBD%2F144854%2F2019/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//PD%2FBD%2F135546%2F2018/PT
oaire.citation.titleGutpt_PT
oaire.fundingStreamPOR_NORTE
oaire.fundingStreamPOR_NORTE
person.familyNameCravo
person.givenNameMarília
person.identifier.orcid0000-0001-8309-4599
person.identifier.scopus-author-id35551480200
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
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project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
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