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...

Descripción completa

Detalles Bibliográficos
Autores: Orozco, Carlos Alberto, Martínez Bosch, Neus, Enrique Guerrero, Pedro, Vinaixa Forner, Judith, 1991-, Dalotto-Moreno, Tomás, Iglesias García, Mar, Moreno, Mireia, Djurec, Magdolna, Poirier, Françoise, Gabius, Hans J., Fernández-Zapico, Martin E., Hwang, Rosa F., Guerra, Carmen, Rabinovich, Gabriel A., Navarro Medrano, Pilar
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2018
País:España
Institución:Universitat Pompeu Fabra
Repositorio:Repositorio Digital de la UPF
OAI Identifier:oai:repositori.upf.edu:10230/36283
Acceso en línea:http://hdl.handle.net/10230/36283
http://dx.doi.org/10.1073/pnas.1722434115
Access Level:acceso abierto
Palabra clave:Galectin-1
Pancreatic cancer
Pancreatic stellate cells
Tumor immunity
Tumor microenvironment
id ES_4ddd66c765d141f6bb70cbfd1850aed2
oai_identifier_str oai:repositori.upf.edu:10230/36283
network_acronym_str ES
network_name_str España
repository_id_str
spelling Targeting galectin-1 inhibits pancreatic cancer progression by modulating tumor-stroma crosstalkOrozco, Carlos AlbertoMartínez Bosch, NeusEnrique Guerrero, PedroVinaixa Forner, Judith, 1991-Dalotto-Moreno, TomásIglesias García, MarMoreno, MireiaDjurec, MagdolnaPoirier, FrançoiseGabius, Hans J.Fernández-Zapico, Martin E.Hwang, Rosa F.Guerra, CarmenRabinovich, Gabriel A.Navarro Medrano, PilarGalectin-1Pancreatic cancerPancreatic stellate cellsTumor immunityTumor microenvironmentPancreatic 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.National Academy of Sciences201920192018info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/36283http://dx.doi.org/10.1073/pnas.1722434115reponame:Repositorio Digital de la UPFinstname:Universitat Pompeu FabraInglésProceedings of the National Academy of Sciences of the United States of America. 2018 Apr 17;115(16):E3769-78© National Academy of Sciencesinfo:eu-repo/semantics/openAccessoai:repositori.upf.edu:10230/362832026-06-12T07:21:37Z
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 Alberto
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 Alberto
Martínez Bosch, Neus
Enrique Guerrero, Pedro
Vinaixa Forner, Judith, 1991-
Dalotto-Moreno, Tomás
Iglesias García, Mar
Moreno, Mireia
Djurec, Magdolna
Poirier, Françoise
Gabius, Hans J.
Fernández-Zapico, Martin E.
Hwang, Rosa F.
Guerra, Carmen
Rabinovich, Gabriel A.
Navarro Medrano, Pilar
author Orozco, Carlos Alberto
author_facet Orozco, Carlos Alberto
Martínez Bosch, Neus
Enrique Guerrero, Pedro
Vinaixa Forner, Judith, 1991-
Dalotto-Moreno, Tomás
Iglesias García, Mar
Moreno, Mireia
Djurec, Magdolna
Poirier, Françoise
Gabius, Hans J.
Fernández-Zapico, Martin E.
Hwang, Rosa F.
Guerra, Carmen
Rabinovich, Gabriel A.
Navarro Medrano, Pilar
author_role author
author2 Martínez Bosch, Neus
Enrique Guerrero, Pedro
Vinaixa Forner, Judith, 1991-
Dalotto-Moreno, Tomás
Iglesias García, Mar
Moreno, Mireia
Djurec, Magdolna
Poirier, Françoise
Gabius, Hans J.
Fernández-Zapico, Martin 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.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
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
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10230/36283
http://dx.doi.org/10.1073/pnas.1722434115
url http://hdl.handle.net/10230/36283
http://dx.doi.org/10.1073/pnas.1722434115
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Proceedings of the National Academy of Sciences of the United States of America. 2018 Apr 17;115(16):E3769-78
dc.rights.none.fl_str_mv © National Academy of Sciences
info:eu-repo/semantics/openAccess
rights_invalid_str_mv © National Academy of Sciences
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 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:Repositorio Digital de la UPF
instname:Universitat Pompeu Fabra
instname_str Universitat Pompeu Fabra
reponame_str Repositorio Digital de la UPF
collection Repositorio Digital de la UPF
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869407719815905280
score 15,811543

Similares en LA Referencia