Extracellular vesicles from pancreatic cancer stem cells lead an intratumor communication network (EVNet) to fuel tumour progression
| Autor(a) principal: | |
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| Data de Publicação: | 2022 |
| Outros Autores: | , , , , , , , , , , , , , , , , , , , , , , , , |
| Tipo de documento: | Artigo |
| Idioma: | eng |
| Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
| Texto Completo: | http://hdl.handle.net/10451/53076 |
Resumo: | © 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/. |
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Extracellular vesicles from pancreatic cancer stem cells lead an intratumor communication network (EVNet) to fuel tumour progressionCarcinogenesisCell biologyMolecular carcinogenesisPancreatic cancer© 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/.Objective: 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.The 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.BMJ Publishing Group Ltd.Repositório da Universidade de LisboaRuivo, Carolina F.Bastos, NunoAdem, BarbaraBatista, InesDuraes, CeciliaMelo, Carlos A.Castaldo, Stephanie A.Campos‐Laborie, FranciscoMoutinho-Ribeiro, PedroMorão, BarbaraCosta-Pinto, AnaSilva, SoraiaOsorio, HugoCiordia, SergioCosta, Jose LuisGoodrich, DavidCavadas, BrunoPereira, LuisaKouzarides, TonyMacedo, GuilhermeMaio, RuiCarneiro, FatimaCravo, MaríliaKalluri, RaghuMachado, Jose CarlosMelo, Sonia A.2022-05-19T14:49:32Z20222022-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10451/53076engGut. 2022 Jan 10;gutjnl-2021-3249940017-574910.1136/gutjnl-2021-3249941468-3288info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-11-08T16:58:39Zoai:repositorio.ul.pt:10451/53076Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T22:04:02.521533Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
| dc.title.none.fl_str_mv |
Extracellular vesicles from pancreatic cancer stem cells lead an intratumor communication network (EVNet) to fuel tumour progression |
| title |
Extracellular vesicles from pancreatic cancer stem cells lead an intratumor communication network (EVNet) to fuel tumour progression |
| spellingShingle |
Extracellular vesicles from pancreatic cancer stem cells lead an intratumor communication network (EVNet) to fuel tumour progression Ruivo, Carolina F. Carcinogenesis Cell biology Molecular carcinogenesis Pancreatic cancer |
| title_short |
Extracellular vesicles from pancreatic cancer stem cells lead an intratumor communication network (EVNet) to fuel tumour progression |
| title_full |
Extracellular vesicles from pancreatic cancer stem cells lead an intratumor communication network (EVNet) to fuel tumour progression |
| title_fullStr |
Extracellular vesicles from pancreatic cancer stem cells lead an intratumor communication network (EVNet) to fuel tumour progression |
| title_full_unstemmed |
Extracellular vesicles from pancreatic cancer stem cells lead an intratumor communication network (EVNet) to fuel tumour progression |
| title_sort |
Extracellular vesicles from pancreatic cancer stem cells lead an intratumor communication network (EVNet) to fuel tumour progression |
| author |
Ruivo, Carolina F. |
| author_facet |
Ruivo, Carolina F. Bastos, Nuno Adem, Barbara Batista, Ines Duraes, Cecilia Melo, Carlos A. Castaldo, Stephanie A. Campos‐Laborie, Francisco Moutinho-Ribeiro, Pedro Morão, Barbara Costa-Pinto, Ana Silva, Soraia Osorio, Hugo Ciordia, Sergio Costa, Jose Luis Goodrich, David Cavadas, Bruno Pereira, Luisa Kouzarides, Tony Macedo, Guilherme Maio, Rui Carneiro, Fatima Cravo, Marília Kalluri, Raghu Machado, Jose Carlos Melo, Sonia A. |
| author_role |
author |
| author2 |
Bastos, Nuno Adem, Barbara Batista, Ines Duraes, Cecilia Melo, Carlos A. Castaldo, Stephanie A. Campos‐Laborie, Francisco Moutinho-Ribeiro, Pedro Morão, Barbara Costa-Pinto, Ana Silva, Soraia Osorio, Hugo Ciordia, Sergio Costa, Jose Luis Goodrich, David Cavadas, Bruno Pereira, Luisa Kouzarides, Tony Macedo, Guilherme Maio, Rui Carneiro, Fatima Cravo, Marília Kalluri, Raghu Machado, Jose Carlos Melo, Sonia A. |
| author2_role |
author author author author author author author author author author author author author author author author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Repositório da Universidade de Lisboa |
| dc.contributor.author.fl_str_mv |
Ruivo, Carolina F. Bastos, Nuno Adem, Barbara Batista, Ines Duraes, Cecilia Melo, Carlos A. Castaldo, Stephanie A. Campos‐Laborie, Francisco Moutinho-Ribeiro, Pedro Morão, Barbara Costa-Pinto, Ana Silva, Soraia Osorio, Hugo Ciordia, Sergio Costa, Jose Luis Goodrich, David Cavadas, Bruno Pereira, Luisa Kouzarides, Tony Macedo, Guilherme Maio, Rui Carneiro, Fatima Cravo, Marília Kalluri, Raghu Machado, Jose Carlos Melo, Sonia A. |
| dc.subject.por.fl_str_mv |
Carcinogenesis Cell biology Molecular carcinogenesis Pancreatic cancer |
| topic |
Carcinogenesis Cell biology Molecular carcinogenesis Pancreatic cancer |
| 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/. |
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2022 |
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2022-05-19T14:49:32Z 2022 2022-01-01T00:00:00Z |
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info:eu-repo/semantics/publishedVersion |
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info:eu-repo/semantics/article |
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eng |
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Gut. 2022 Jan 10;gutjnl-2021-324994 0017-5749 10.1136/gutjnl-2021-324994 1468-3288 |
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BMJ Publishing Group Ltd. |
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BMJ Publishing Group Ltd. |
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