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

Neus Martínez-Bosch, Maite G. Fern̊andez-Barrena, Mireia Moreno, Elena Ortiz-Zapater, Jessica Munn̊e-Collado, Mar Iglesias, Sabine Andr̊e, Hans Joachim Gabius, Rosa F. Hwang, Fraņ Coise Poirier, Carolina Navas, Carmen Guerra, Martin E. Fern̊andez-Zapico, Pilar Navarro

Research output: Contribution to journalArticle

64 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3512-3524
Number of pages13
JournalCancer research
Volume74
Issue number13
DOIs
StatePublished - Jul 1 2014

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Martínez-Bosch, N., Fern̊andez-Barrena, M. G., Moreno, M., Ortiz-Zapater, E., Munn̊e-Collado, J., Iglesias, M., Andr̊e, S., Gabius, H. J., Hwang, R. F., Coise Poirier, F., Navas, C., Guerra, C., Fern̊andez-Zapico, M. E., & Navarro, P. (2014). Galectin-1 drives pancreatic carcinogenesis through stroma remodeling and hedgehog signaling activation. Cancer research, 74(13), 3512-3524. https://doi.org/10.1158/0008-5472.CAN-13-3013