CD73 controls Myosin II-driven invasion, metastasis, and immunosuppression in amoeboid pancreatic cancer cells

Pancreatic ductal adenocarcinoma (PDAC) has a very poor prognosis because of its high propensity to metastasize and its immunosuppressive microenvironment. Using a panel of pancreatic cancer cell lines, three-dimensional (3D) invasion systems, microarray gene signatures, microfluidic devices, mouse...

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Autores: Samain, Remi, Maiques, Oscar, Monger, Joanne, Lam, Hoyin, Candido, Juliana, George, Samantha, Ferrari, Nicola, KohIhammer, Leonie, Lunetto, Sophia, Varela, Adrián, Orgaz, José L., Vilardell, Felip, Olsina, Jorge Juan, Matías-Guiu, Xavier, Sarker, Debashis, Biddle, Adrián, Balkwill, Frances R., Eyles, Jim, Wilkinson, Robert W., Kocher, Hemant M., Calvo, Fernando, Wells, Claire M., Sanz-Moreno, Victoria
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2023
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/348548
Acceso en línea:http://hdl.handle.net/10261/348548
https://api.elsevier.com/content/abstract/scopus_id/85174748321
Access Level:acceso abierto
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spelling CD73 controls Myosin II-driven invasion, metastasis, and immunosuppression in amoeboid pancreatic cancer cellsSamain, RemiMaiques, OscarMonger, JoanneLam, HoyinCandido, JulianaGeorge, SamanthaFerrari, NicolaKohIhammer, LeonieLunetto, SophiaVarela, AdriánOrgaz, José L.Vilardell, FelipOlsina, Jorge JuanMatías-Guiu, XavierSarker, DebashisBiddle, AdriánBalkwill, Frances R.Eyles, JimWilkinson, Robert W.Kocher, Hemant M.Calvo, FernandoWells, Claire M.Sanz-Moreno, VictoriaPancreatic ductal adenocarcinoma (PDAC) has a very poor prognosis because of its high propensity to metastasize and its immunosuppressive microenvironment. Using a panel of pancreatic cancer cell lines, three-dimensional (3D) invasion systems, microarray gene signatures, microfluidic devices, mouse models, and intravital imaging, we demonstrate that ROCK–Myosin II activity in PDAC cells supports a transcriptional program conferring amoeboid invasive and immunosuppressive traits and in vivo metastatic abilities. Moreover, we find that immune checkpoint CD73 is highly expressed in amoeboid PDAC cells and drives their invasive, metastatic, and immunomodulatory traits. Mechanistically, CD73 activates RhoA–ROCK–Myosin II downstream of PI3K. Tissue microarrays of human PDAC biopsies combined with bioinformatic analysis reveal that rounded-amoeboid invasive cells with high CD73–ROCK–Myosin II activity and their immunosuppressive microenvironment confer poor prognosis to patients. We propose targeting amoeboid PDAC cells as a therapeutic strategy.The work was supported by Barts Charity MGU0418 (R.S., O.M., J.M., S.G., and V.S.-M.), Organ-on-a-Chip Network and Emulate Proof of Concept Awards (R.S. and V.S.-M.), Cancer Research UK (CRUK) C33043/A24478 (O.M., L.K., and V.S.-M.), Pancreatic Cancer Research UK Fund (C.M.W.), National Centre for the 3Rs (S.L. and A.B.), The National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London and/or the NIHR Clinical Research Facility (H.L.), and Grant Atracción de Talento Investigador funded by Comunidad de Madrid (J.L.O.).Peer reviewedAmerican Association for the Advancement of ScienceBarts CharityCancer Research UKNational Institute of Mental Health (US)NIHR Biomedical Research Centre (UK)Comunidad de MadridConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202420242023info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10261/348548https://api.elsevier.com/content/abstract/scopus_id/85174748321reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE#2019-T1/BMD-13642/Atracción de Talento InvestigadorScience advancesThe underlying dataset has been published as supplementary material of the article in the publisher platform at 10.1126/sciadv.adi0244http://dx.doi.org/10.1126/sciadv.adi0244Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/3485482026-05-22T06:33:51Z
dc.title.none.fl_str_mv CD73 controls Myosin II-driven invasion, metastasis, and immunosuppression in amoeboid pancreatic cancer cells
title CD73 controls Myosin II-driven invasion, metastasis, and immunosuppression in amoeboid pancreatic cancer cells
spellingShingle CD73 controls Myosin II-driven invasion, metastasis, and immunosuppression in amoeboid pancreatic cancer cells
Samain, Remi
title_short CD73 controls Myosin II-driven invasion, metastasis, and immunosuppression in amoeboid pancreatic cancer cells
title_full CD73 controls Myosin II-driven invasion, metastasis, and immunosuppression in amoeboid pancreatic cancer cells
title_fullStr CD73 controls Myosin II-driven invasion, metastasis, and immunosuppression in amoeboid pancreatic cancer cells
title_full_unstemmed CD73 controls Myosin II-driven invasion, metastasis, and immunosuppression in amoeboid pancreatic cancer cells
title_sort CD73 controls Myosin II-driven invasion, metastasis, and immunosuppression in amoeboid pancreatic cancer cells
dc.creator.none.fl_str_mv Samain, Remi
Maiques, Oscar
Monger, Joanne
Lam, Hoyin
Candido, Juliana
George, Samantha
Ferrari, Nicola
KohIhammer, Leonie
Lunetto, Sophia
Varela, Adrián
Orgaz, José L.
Vilardell, Felip
Olsina, Jorge Juan
Matías-Guiu, Xavier
Sarker, Debashis
Biddle, Adrián
Balkwill, Frances R.
Eyles, Jim
Wilkinson, Robert W.
Kocher, Hemant M.
Calvo, Fernando
Wells, Claire M.
Sanz-Moreno, Victoria
author Samain, Remi
author_facet Samain, Remi
Maiques, Oscar
Monger, Joanne
Lam, Hoyin
Candido, Juliana
George, Samantha
Ferrari, Nicola
KohIhammer, Leonie
Lunetto, Sophia
Varela, Adrián
Orgaz, José L.
Vilardell, Felip
Olsina, Jorge Juan
Matías-Guiu, Xavier
Sarker, Debashis
Biddle, Adrián
Balkwill, Frances R.
Eyles, Jim
Wilkinson, Robert W.
Kocher, Hemant M.
Calvo, Fernando
Wells, Claire M.
Sanz-Moreno, Victoria
author_role author
author2 Maiques, Oscar
Monger, Joanne
Lam, Hoyin
Candido, Juliana
George, Samantha
Ferrari, Nicola
KohIhammer, Leonie
Lunetto, Sophia
Varela, Adrián
Orgaz, José L.
Vilardell, Felip
Olsina, Jorge Juan
Matías-Guiu, Xavier
Sarker, Debashis
Biddle, Adrián
Balkwill, Frances R.
Eyles, Jim
Wilkinson, Robert W.
Kocher, Hemant M.
Calvo, Fernando
Wells, Claire M.
Sanz-Moreno, Victoria
author2_role 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 Barts Charity
Cancer Research UK
National Institute of Mental Health (US)
NIHR Biomedical Research Centre (UK)
Comunidad de Madrid
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
description Pancreatic ductal adenocarcinoma (PDAC) has a very poor prognosis because of its high propensity to metastasize and its immunosuppressive microenvironment. Using a panel of pancreatic cancer cell lines, three-dimensional (3D) invasion systems, microarray gene signatures, microfluidic devices, mouse models, and intravital imaging, we demonstrate that ROCK–Myosin II activity in PDAC cells supports a transcriptional program conferring amoeboid invasive and immunosuppressive traits and in vivo metastatic abilities. Moreover, we find that immune checkpoint CD73 is highly expressed in amoeboid PDAC cells and drives their invasive, metastatic, and immunomodulatory traits. Mechanistically, CD73 activates RhoA–ROCK–Myosin II downstream of PI3K. Tissue microarrays of human PDAC biopsies combined with bioinformatic analysis reveal that rounded-amoeboid invasive cells with high CD73–ROCK–Myosin II activity and their immunosuppressive microenvironment confer poor prognosis to patients. We propose targeting amoeboid PDAC cells as a therapeutic strategy.
publishDate 2023
dc.date.none.fl_str_mv 2023
2024
2024
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/348548
https://api.elsevier.com/content/abstract/scopus_id/85174748321
url http://hdl.handle.net/10261/348548
https://api.elsevier.com/content/abstract/scopus_id/85174748321
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
2019-T1/BMD-13642/Atracción de Talento Investigador
Science advances
The underlying dataset has been published as supplementary material of the article in the publisher platform at 10.1126/sciadv.adi0244
http://dx.doi.org/10.1126/sciadv.adi0244
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv American Association for the Advancement of Science
publisher.none.fl_str_mv American Association for the Advancement of Science
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,811543

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