TY - JOUR
T1 - Galectin-1 drives pancreatic carcinogenesis through stroma remodeling and hedgehog signaling activation
AU - Martínez-Bosch, Neus
AU - Fern̊andez-Barrena, Maite G.
AU - Moreno, Mireia
AU - Ortiz-Zapater, Elena
AU - Munn̊e-Collado, Jessica
AU - Iglesias, Mar
AU - Andr̊e, Sabine
AU - Gabius, Hans Joachim
AU - Hwang, Rosa F.
AU - Coise Poirier, Fraņ
AU - Navas, Carolina
AU - Guerra, Carmen
AU - Fern̊andez-Zapico, Martin E.
AU - Navarro, Pilar
PY - 2014/7/1
Y1 - 2014/7/1
N2 - 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 therapeutic 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.
AB - 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 therapeutic 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.
UR - http://www.scopus.com/inward/record.url?scp=84903955050&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84903955050&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-13-3013
DO - 10.1158/0008-5472.CAN-13-3013
M3 - Article
C2 - 24812270
AN - SCOPUS:84903955050
SN - 0008-5472
VL - 74
SP - 3512
EP - 3524
JO - Cancer Research
JF - Cancer Research
IS - 13
ER -