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

Autores
Orozco, Carlos A.; Martinez Bosch, Neus; Guerrero, Pedro E.; Vinaixa, Judith; D'alotto Moreno, Tomas; Iglesias, Mar; Moreno, Mireia; Djurec, Magdolna; Poirier, Françoise; Gabius, Hans Joachim; Fernandez Zapico, Martin Ernesto; Hwang, Rosa F.; Guerra, Carmen; Rabinovich, Gabriel Adrián; Navarro, Pilar
Año de publicación
2018
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
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.
Fil: Orozco, Carlos A.. Institut Hospital del Mar d'Investigacions Mèdiques; España
Fil: Martinez Bosch, Neus. Institut Hospital del Mar d'Investigacions Mèdiques; España
Fil: Guerrero, Pedro E.. Universidad de Girona; España. Institut Hospital del Mar d'Investigacions Mèdiques; España
Fil: Vinaixa, Judith. Institut Hospital del Mar d'Investigacions Mèdiques; España
Fil: D'alotto Moreno, Tomas. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Fil: Iglesias, Mar. Universitat Autònoma de Barcelona; España. Institut Hospital del Mar d'Investigacions Mèdiques; España
Fil: Moreno, Mireia. Institut Hospital del Mar d'Investigacions Mèdiques; España
Fil: Djurec, Magdolna. Centro Nacional de Investigaciones Oncológicas; España
Fil: Poirier, Françoise. Université Paris Diderot - Paris 7; Francia
Fil: Gabius, Hans Joachim. Ludwig Maximilians Universitat; Alemania
Fil: Fernandez Zapico, Martin Ernesto. Mayo Clinic; Estados Unidos
Fil: Hwang, Rosa F.. Texas A&M University; Estados Unidos
Fil: Guerra, Carmen. Centro Nacional de Investigaciones Oncológicas; España
Fil: Rabinovich, Gabriel Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina
Fil: Navarro, Pilar. Consejo Superior de Investigaciones Científicas; España. Centro Nacional de Investigaciones Oncológicas; España
Materia
GALECTIN-1
PANCREATIC CANCER
PANCREATIC STELLATE CELLS
TUMOR IMMUNITY
TUMOR MICROENVIRONMENT
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/85367
Acceder
id CONICETDig_47b51bd694fccb4d378f013d822e7308
oai_identifier_str oai:ri.conicet.gov.ar:11336/85367
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Targeting galectin-1 inhibits pancreatic cancer progression by modulating tumor–stroma crosstalkOrozco, Carlos A.Martinez Bosch, NeusGuerrero, Pedro E.Vinaixa, JudithD'alotto Moreno, TomasIglesias, MarMoreno, MireiaDjurec, MagdolnaPoirier, FrançoiseGabius, Hans JoachimFernandez Zapico, Martin ErnestoHwang, Rosa F.Guerra, CarmenRabinovich, Gabriel AdriánNavarro, PilarGALECTIN-1PANCREATIC CANCERPANCREATIC STELLATE CELLSTUMOR IMMUNITYTUMOR MICROENVIRONMENThttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Pancreatic 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.Fil: Orozco, Carlos A.. Institut Hospital del Mar d'Investigacions Mèdiques; EspañaFil: Martinez Bosch, Neus. Institut Hospital del Mar d'Investigacions Mèdiques; EspañaFil: Guerrero, Pedro E.. Universidad de Girona; España. Institut Hospital del Mar d'Investigacions Mèdiques; EspañaFil: Vinaixa, Judith. Institut Hospital del Mar d'Investigacions Mèdiques; EspañaFil: D'alotto Moreno, Tomas. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Iglesias, Mar. Universitat Autònoma de Barcelona; España. Institut Hospital del Mar d'Investigacions Mèdiques; EspañaFil: Moreno, Mireia. Institut Hospital del Mar d'Investigacions Mèdiques; EspañaFil: Djurec, Magdolna. Centro Nacional de Investigaciones Oncológicas; EspañaFil: Poirier, Françoise. Université Paris Diderot - Paris 7; FranciaFil: Gabius, Hans Joachim. Ludwig Maximilians Universitat; AlemaniaFil: Fernandez Zapico, Martin Ernesto. Mayo Clinic; Estados UnidosFil: Hwang, Rosa F.. Texas A&M University; Estados UnidosFil: Guerra, Carmen. Centro Nacional de Investigaciones Oncológicas; EspañaFil: Rabinovich, Gabriel Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; ArgentinaFil: Navarro, Pilar. Consejo Superior de Investigaciones Científicas; España. Centro Nacional de Investigaciones Oncológicas; EspañaNational Academy of Sciences2018-04info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/85367Orozco, Carlos A.; Martinez Bosch, Neus; Guerrero, Pedro E.; Vinaixa, Judith; D'alotto Moreno, Tomas; et al.; Targeting galectin-1 inhibits pancreatic cancer progression by modulating tumor–stroma crosstalk; National Academy of Sciences; Proceedings of the National Academy of Sciences of The United States of America; 115; 16; 4-2018; E3769-E37780027-8424CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.pnas.org/content/115/16/E3769.longinfo:eu-repo/semantics/altIdentifier/doi/10.1073/pnas.1722434115info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:59:49Zoai:ri.conicet.gov.ar:11336/85367instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-03 09:59:50.006CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
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.
GALECTIN-1
PANCREATIC CANCER
PANCREATIC STELLATE CELLS
TUMOR IMMUNITY
TUMOR MICROENVIRONMENT
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.
Martinez Bosch, Neus
Guerrero, Pedro E.
Vinaixa, Judith
D'alotto Moreno, Tomas
Iglesias, Mar
Moreno, Mireia
Djurec, Magdolna
Poirier, Françoise
Gabius, Hans Joachim
Fernandez Zapico, Martin Ernesto
Hwang, Rosa F.
Guerra, Carmen
Rabinovich, Gabriel Adrián
Navarro, Pilar
author Orozco, Carlos A.
author_facet Orozco, Carlos A.
Martinez Bosch, Neus
Guerrero, Pedro E.
Vinaixa, Judith
D'alotto Moreno, Tomas
Iglesias, Mar
Moreno, Mireia
Djurec, Magdolna
Poirier, Françoise
Gabius, Hans Joachim
Fernandez Zapico, Martin Ernesto
Hwang, Rosa F.
Guerra, Carmen
Rabinovich, Gabriel Adrián
Navarro, Pilar
author_role author
author2 Martinez Bosch, Neus
Guerrero, Pedro E.
Vinaixa, Judith
D'alotto Moreno, Tomas
Iglesias, Mar
Moreno, Mireia
Djurec, Magdolna
Poirier, Françoise
Gabius, Hans Joachim
Fernandez Zapico, Martin Ernesto
Hwang, Rosa F.
Guerra, Carmen
Rabinovich, Gabriel Adrián
Navarro, Pilar
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv GALECTIN-1
PANCREATIC CANCER
PANCREATIC STELLATE CELLS
TUMOR IMMUNITY
TUMOR MICROENVIRONMENT
topic GALECTIN-1
PANCREATIC CANCER
PANCREATIC STELLATE CELLS
TUMOR IMMUNITY
TUMOR MICROENVIRONMENT
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv 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.
Fil: Orozco, Carlos A.. Institut Hospital del Mar d'Investigacions Mèdiques; España
Fil: Martinez Bosch, Neus. Institut Hospital del Mar d'Investigacions Mèdiques; España
Fil: Guerrero, Pedro E.. Universidad de Girona; España. Institut Hospital del Mar d'Investigacions Mèdiques; España
Fil: Vinaixa, Judith. Institut Hospital del Mar d'Investigacions Mèdiques; España
Fil: D'alotto Moreno, Tomas. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Fil: Iglesias, Mar. Universitat Autònoma de Barcelona; España. Institut Hospital del Mar d'Investigacions Mèdiques; España
Fil: Moreno, Mireia. Institut Hospital del Mar d'Investigacions Mèdiques; España
Fil: Djurec, Magdolna. Centro Nacional de Investigaciones Oncológicas; España
Fil: Poirier, Françoise. Université Paris Diderot - Paris 7; Francia
Fil: Gabius, Hans Joachim. Ludwig Maximilians Universitat; Alemania
Fil: Fernandez Zapico, Martin Ernesto. Mayo Clinic; Estados Unidos
Fil: Hwang, Rosa F.. Texas A&M University; Estados Unidos
Fil: Guerra, Carmen. Centro Nacional de Investigaciones Oncológicas; España
Fil: Rabinovich, Gabriel Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina
Fil: Navarro, Pilar. Consejo Superior de Investigaciones Científicas; España. Centro Nacional de Investigaciones Oncológicas; España
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 2018-04
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/85367
Orozco, Carlos A.; Martinez Bosch, Neus; Guerrero, Pedro E.; Vinaixa, Judith; D'alotto Moreno, Tomas; et al.; Targeting galectin-1 inhibits pancreatic cancer progression by modulating tumor–stroma crosstalk; National Academy of Sciences; Proceedings of the National Academy of Sciences of The United States of America; 115; 16; 4-2018; E3769-E3778
0027-8424
CONICET Digital
CONICET
url http://hdl.handle.net/11336/85367
identifier_str_mv Orozco, Carlos A.; Martinez Bosch, Neus; Guerrero, Pedro E.; Vinaixa, Judith; D'alotto Moreno, Tomas; et al.; Targeting galectin-1 inhibits pancreatic cancer progression by modulating tumor–stroma crosstalk; National Academy of Sciences; Proceedings of the National Academy of Sciences of The United States of America; 115; 16; 4-2018; E3769-E3778
0027-8424
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://www.pnas.org/content/115/16/E3769.long
info:eu-repo/semantics/altIdentifier/doi/10.1073/pnas.1722434115
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv National Academy of Sciences
publisher.none.fl_str_mv National Academy of Sciences
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.13397

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