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Proc Natl Acad Sci U S A. 2018 Apr 17;115(16):E3769-E3778. doi: 10.1073/pnas.1722434115. Epub 2018 Apr 3.

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

Author information

1
Cancer Research Program, Hospital del Mar Medical Research Institute, 08003 Barcelona, Spain.
2
Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, C1428ADN Buenos Aires, Argentina.
3
Department of Pathology, Autonomous University of Barcelona, 08005 Barcelona, Spain.
4
Centro de Investigación Biomédica en Red de Cáncer, Hospital del Mar, 08005 Barcelona, Spain.
5
Molecular Oncology Program, Centro Nacional de Investigaciones Oncológicas, 28029 Madrid, Spain.
6
Jacques Monod Institute, Paris Diderot University, UMR CNRS 7592, 75205 Paris Cedex 013, France.
7
Institut für Physiologische Chemie, Tierärztliche Fakultät, Ludwig-Maximilians-Universität, D-80539 Munich, Germany.
8
Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, MN 55905.
9
Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77230.
10
Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, C1428ADN Buenos Aires, Argentina; gabyrabi@gmail.com pnavarro@imim.es.
11
Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, C1428 Buenos Aires, Argentina.
12
Cancer Research Program, Hospital del Mar Medical Research Institute, 08003 Barcelona, Spain; gabyrabi@gmail.com pnavarro@imim.es.
13
Institute of Biomedical Research of Barcelona-Consejo Superior de Investigaciones Cientificas, 080036 Barcelona, Spain.

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.

KEYWORDS:

galectin-1; pancreatic cancer; pancreatic stellate cells; tumor immunity; tumor microenvironment

PMID:
29615514
PMCID:
PMC5910865
DOI:
10.1073/pnas.1722434115
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors declare no conflict of interest.

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