Galectin-1 drives pancreatic carcinogenesis through stroma remodeling and Hedgehog signaling activation. - Université Paris Cité Accéder directement au contenu
Article Dans Une Revue Cancer Research Année : 2014

Galectin-1 drives pancreatic carcinogenesis through stroma remodeling and Hedgehog signaling activation.

Résumé

: Despite some advances, pancreatic ductal adenocarcinoma (PDAC) remains generally refractory to current treatments. Desmoplastic stroma, a consistent hallmark of PDAC, has emerged as a major source of therapeutuic resistance and thus potentially promising targets for improved treatment. The glycan-binding protein galectin-1 (Gal1) is highly expressed in PDAC stroma but its roles there have not been studied. Here we report functions and molecular pathways of Gal1 that mediate its oncogenic properties in this setting. Genetic ablation of Gal1 in a mouse model of PDAC (EIa-myc mice) dampened tumor progression by inhibiting proliferation, angiogenesis, desmoplasic reaction and by stimulating a tumor-associated immune response, yielding a 20% increase in relative lifesplan. Cellular analyses in vitro and in vivo suggested these effects were mediated through the tumor microenvironment. Importantly, acinar-to-ductal metaplasia, a crucial step for initiation of PDAC, was found to be regulated by Gal1. Mechanistic investigations revealed that Gal1 promoted Hedgehog pathway signaling, in PDAC cells and stromal fibroblasts as well as in Ela-myc tumors. Taken together, our findings establish a function for Gal1 in tumor-stroma crosstalk in PDAC and provide a preclinical rationale for Gal1 targeting as a microenvironment-based therapeutic strategy.

Dates et versions

hal-00994994 , version 1 (22-05-2014)

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Neus Martinez-Bosch, Maite G Fernandez-Barrena, Mireia Moreno, Elena Ortiz-Zapater, Jessica Munne-Collado, et al.. Galectin-1 drives pancreatic carcinogenesis through stroma remodeling and Hedgehog signaling activation.. Cancer Research, 2014, epub ahead of print. ⟨10.1158/0008-5472.CAN-13-3013⟩. ⟨hal-00994994⟩
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