Targeting galectin-1 inhibits pancreatic cancer progression by modulating tumor–stroma crosstalk

Pancreatic ductal adenocarcinoma (PDA) remains one of the most lethal tumor types, with extremely low survival rates due to late diagnosis and resistance to standard therapies. A more comprehensive understanding of the complexity of PDA pathobiology, and especially of the role of the tumor microenvi...

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Autores: Orozco, Carlos A., Martínez-Bosch, Neus, Guerrero, Pedro E., Vinaixa, Judith, Dalotto-Moreno, Tomás, Iglesias, Mar, Moreno-Estellés, Mireia, Djurec, Magdolna, Poirier, Françoise, Gabius, Hans-Joachim, Fernández-Zapico, E., Hwang, Rosa F., Guerra, Carmen, Rabinovich, Gabriel A., Navarro Medrano, Pilar
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2018
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/177188
Acceso en línea:http://hdl.handle.net/10261/177188
http://hdl.handle.net/10261/177175
Access Level:acceso abierto
Palabra clave:Pancreatic cancer
Galectin-1
Tumor microenvironment
Tumor immunity
Pancreatic stellate cells
id ES_997903b6fbe3f9c4e5ed2ece7f96e31e
oai_identifier_str oai:digital.csic.es:10261/177188
network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv Targeting galectin-1 inhibits pancreatic cancer progression by modulating tumor–stroma crosstalk
title Targeting galectin-1 inhibits pancreatic cancer progression by modulating tumor–stroma crosstalk
spellingShingle Targeting galectin-1 inhibits pancreatic cancer progression by modulating tumor–stroma crosstalk
Orozco, Carlos A.
Pancreatic cancer
Galectin-1
Tumor microenvironment
Tumor immunity
Pancreatic stellate cells
title_short Targeting galectin-1 inhibits pancreatic cancer progression by modulating tumor–stroma crosstalk
title_full Targeting galectin-1 inhibits pancreatic cancer progression by modulating tumor–stroma crosstalk
title_fullStr Targeting galectin-1 inhibits pancreatic cancer progression by modulating tumor–stroma crosstalk
title_full_unstemmed Targeting galectin-1 inhibits pancreatic cancer progression by modulating tumor–stroma crosstalk
title_sort Targeting galectin-1 inhibits pancreatic cancer progression by modulating tumor–stroma crosstalk
dc.creator.none.fl_str_mv Orozco, Carlos A.
Martínez-Bosch, Neus
Guerrero, Pedro E.
Vinaixa, Judith
Dalotto-Moreno, Tomás
Iglesias, Mar
Moreno-Estellés, Mireia
Djurec, Magdolna
Poirier, Françoise
Gabius, Hans-Joachim
Fernández-Zapico, E.
Hwang, Rosa F.
Guerra, Carmen
Rabinovich, Gabriel A.
Navarro Medrano, Pilar
author Orozco, Carlos A.
author_facet Orozco, Carlos A.
Martínez-Bosch, Neus
Guerrero, Pedro E.
Vinaixa, Judith
Dalotto-Moreno, Tomás
Iglesias, Mar
Moreno-Estellés, Mireia
Djurec, Magdolna
Poirier, Françoise
Gabius, Hans-Joachim
Fernández-Zapico, E.
Hwang, Rosa F.
Guerra, Carmen
Rabinovich, Gabriel A.
Navarro Medrano, Pilar
author_role author
author2 Martínez-Bosch, Neus
Guerrero, Pedro E.
Vinaixa, Judith
Dalotto-Moreno, Tomás
Iglesias, Mar
Moreno-Estellés, Mireia
Djurec, Magdolna
Poirier, Françoise
Gabius, Hans-Joachim
Fernández-Zapico, E.
Hwang, Rosa F.
Guerra, Carmen
Rabinovich, Gabriel A.
Navarro Medrano, Pilar
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Economía y Competitividad (España)
Instituto de Salud Carlos III
European Commission
Asociación Española de Pancreatología
Asociación Cáncer de Páncreas (España)
Generalitat de Catalunya
Mayo Clinic
Colciencias (Colombia)
La Caixa
Agencia Nacional de Promoción Científica y Tecnológica (Argentina)
Universidad de Buenos Aires
Bunge & Born Foundation
Fundación Sales
Consejo Nacional de Investigaciones Científicas y Técnicas (Argentina)
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Pancreatic cancer
Galectin-1
Tumor microenvironment
Tumor immunity
Pancreatic stellate cells
topic Pancreatic cancer
Galectin-1
Tumor microenvironment
Tumor immunity
Pancreatic stellate cells
description Pancreatic ductal adenocarcinoma (PDA) remains one of the most lethal tumor types, with extremely low survival rates due to late diagnosis and resistance to standard therapies. A more comprehensive understanding of the complexity of PDA pathobiology, and especially of the role of the tumor microenvironment in disease progression, should pave the way for therapies to improve patient response rates. In this study, we identify galectin-1 (Gal1), a glycan-binding protein that is highly overexpressed in PDA stroma, as a major driver of pancreatic cancer progression. Genetic deletion of Gal1 in a Kras-driven mouse model of PDA (Ela-KrasG12Vp53−/−) results in a significant increase in survival through mechanisms involving decreased stroma activation, attenuated vascularization, and enhanced T cell infiltration leading to diminished metastasis rates. In a human setting, human pancreatic stellate cells (HPSCs) promote cancer proliferation, migration, and invasion via Gal1-driven pathways. Moreover, in vivo orthotopic coinjection of pancreatic tumor cells with Gal1-depleted HPSCs leads to impaired tumor formation and metastasis in mice. Gene-expression analyses of pancreatic tumor cells exposed to Gal1 reveal modulation of multiple regulatory pathways involved in tumor progression. Thus, Gal1 hierarchically regulates different events implicated in PDA biology including tumor cell proliferation, invasion, angiogenesis, inflammation, and metastasis, highlighting the broad therapeutic potential of Gal1-specific inhibitors, either alone or in combination with other therapeutic modalities.
publishDate 2018
dc.date.none.fl_str_mv 2018
2019
2019
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/10261/177188
http://hdl.handle.net/10261/177175
url http://hdl.handle.net/10261/177188
http://hdl.handle.net/10261/177175
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv https://doi.org/10.1073/pnas.1722434115
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv National Academy of Sciences (U.S.)
publisher.none.fl_str_mv National Academy of Sciences (U.S.)
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
_version_ 1869414292123549696
spelling Targeting galectin-1 inhibits pancreatic cancer progression by modulating tumor–stroma crosstalkOrozco, Carlos A.Martínez-Bosch, NeusGuerrero, Pedro E.Vinaixa, JudithDalotto-Moreno, TomásIglesias, MarMoreno-Estellés, MireiaDjurec, MagdolnaPoirier, FrançoiseGabius, Hans-JoachimFernández-Zapico, E.Hwang, Rosa F.Guerra, CarmenRabinovich, Gabriel A.Navarro Medrano, PilarPancreatic cancerGalectin-1Tumor microenvironmentTumor immunityPancreatic stellate cellsPancreatic ductal adenocarcinoma (PDA) remains one of the most lethal tumor types, with extremely low survival rates due to late diagnosis and resistance to standard therapies. A more comprehensive understanding of the complexity of PDA pathobiology, and especially of the role of the tumor microenvironment in disease progression, should pave the way for therapies to improve patient response rates. In this study, we identify galectin-1 (Gal1), a glycan-binding protein that is highly overexpressed in PDA stroma, as a major driver of pancreatic cancer progression. Genetic deletion of Gal1 in a Kras-driven mouse model of PDA (Ela-KrasG12Vp53−/−) results in a significant increase in survival through mechanisms involving decreased stroma activation, attenuated vascularization, and enhanced T cell infiltration leading to diminished metastasis rates. In a human setting, human pancreatic stellate cells (HPSCs) promote cancer proliferation, migration, and invasion via Gal1-driven pathways. Moreover, in vivo orthotopic coinjection of pancreatic tumor cells with Gal1-depleted HPSCs leads to impaired tumor formation and metastasis in mice. Gene-expression analyses of pancreatic tumor cells exposed to Gal1 reveal modulation of multiple regulatory pathways involved in tumor progression. Thus, Gal1 hierarchically regulates different events implicated in PDA biology including tumor cell proliferation, invasion, angiogenesis, inflammation, and metastasis, highlighting the broad therapeutic potential of Gal1-specific inhibitors, either alone or in combination with other therapeutic modalities.This work was supported by Spanish Ministry of Economy and Competitiveness/ISCIII-FEDER Grants PI14/00125 and PI17/00199, the Carmen Delgado/Miguel Pérez-Mateo Asociación Española de Pancreatología/ Asociación Cáncer de Páncreas 2016 Grant, and Generalitat de Catalunya Grant 2014/SGR/143 (to P.N.). M.E.F.-Z. was supported by Mayo Clinic Pancreatic Specialized Program of Research Excellence Grant P50 CA102701 and Mayo Clinic Center for Cell Signaling in Gastroenterology Grant P30 DK84567. C.A.O. was supported by the International PhD Studies Fellowship Créditos Beca Francisco José de Caldas from the Colombian Administrative Department of Science, Technology and Innovation (Colciencias). M.D. was supported by a fellowship from La Caixa International Fellowship Program. G.A.R. was supported by Argentinean Agency for Promotion of Science and Technology Grant PICT 2014-3687 and by grants from the University of Buenos Aires, the Sales Foundation, and the Bunge and Born Foundation. T.D.-M. is a postdoctoral fellow supported by the Argentine National Scientific and Technical Research Council.Peer reviewedNational Academy of Sciences (U.S.)Ministerio de Economía y Competitividad (España)Instituto de Salud Carlos IIIEuropean CommissionAsociación Española de PancreatologíaAsociación Cáncer de Páncreas (España)Generalitat de CatalunyaMayo ClinicColciencias (Colombia)La CaixaAgencia Nacional de Promoción Científica y Tecnológica (Argentina)Universidad de Buenos AiresBunge & Born FoundationFundación SalesConsejo Nacional de Investigaciones Científicas y Técnicas (Argentina)Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]201920192018info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/177188http://hdl.handle.net/10261/177175reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Ingléshttps://doi.org/10.1073/pnas.1722434115Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/1771882026-05-22T06:33:51Z
score 15,811543

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