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

Carlos A. Orozco, Neus Martinez-Bosch, Pedro E. Guerrero, Judith Vinaixa, Tomás Dalotto-Moreno, Mar Iglesias, Mireia Moreno, Magdolna Djurec, Françoise Poirier, Hans Joachim Gabius, Martin E. Fernandez-Zapico, Rosa F. Hwang, Carmen Guerra, Gabriel A. Rabinovich, Pilar Navarro

Research output: Contribution to journalReview articlepeer-review

39 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)E3769-E3778
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number16
DOIs
StatePublished - Apr 17 2018

Keywords

  • Galectin-1
  • Pancreatic cancer
  • Pancreatic stellate cells
  • Tumor immunity
  • Tumor microenvironment

ASJC Scopus subject areas

  • General

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