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

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dc.contributor.author Orozco, Carlos Alberto
dc.contributor.author Martínez Bosch, Neus
dc.contributor.author Enrique Guerrero, Pedro
dc.contributor.author Vinaixa Forner, Judith, 1991-
dc.contributor.author Dalotto-Moreno, Tomás
dc.contributor.author Iglesias García, Mar
dc.contributor.author Moreno, Mireia
dc.contributor.author Djurec, Magdolna
dc.contributor.author Poirier, Françoise
dc.contributor.author Gabius, Hans J.
dc.contributor.author Fernández-Zapico, Martin E.
dc.contributor.author Hwang, Rosa F.
dc.contributor.author Guerra, Carmen
dc.contributor.author Rabinovich, Gabriel A.
dc.contributor.author Navarro Medrano, Pilar
dc.date.accessioned 2019-01-16T08:10:02Z
dc.date.available 2019-01-16T08:10:02Z
dc.date.issued 2018
dc.identifier.citation Orozco CA, Martinez-Bosch N, Guerrero PE, Vinaixa J, Dalotto-Moreno T, Iglesias M. et al. Targeting galectin-1 inhibits pancreatic cancer progression by modulating tumor-stroma crosstalk. Proc Natl Acad Sci U S A. 2018 Apr 17;115(16):E3769-E3778. DOI: 10.1073/pnas.1722434115
dc.identifier.issn 0027-8424
dc.identifier.uri http://hdl.handle.net/10230/36283
dc.description.abstract 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.
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher National Academy of Sciences
dc.relation.ispartof Proceedings of the National Academy of Sciences of the United States of America. 2018 Apr 17;115(16):E3769-78
dc.rights © National Academy of Sciences
dc.title Targeting galectin-1 inhibits pancreatic cancer progression by modulating tumor-stroma crosstalk
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.1073/pnas.1722434115
dc.subject.keyword Galectin-1
dc.subject.keyword Pancreatic cancer
dc.subject.keyword Pancreatic stellate cells
dc.subject.keyword Tumor immunity
dc.subject.keyword Tumor microenvironment
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/acceptedVersion

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