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.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.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.doi http://dx.doi.org/10.1073/pnas.1722434115
• dc.identifier.issn 0027-8424
• dc.identifier.uri http://hdl.handle.net/10230/36283
• 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.rights.accessRights info:eu-repo/semantics/openAccess
• 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.title Targeting galectin-1 inhibits pancreatic cancer progression by modulating tumor-stroma crosstalk
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/acceptedVersion