title: Galectin-1 drives pancreatic carcinogenesis through stroma remodeling and Hedgehog signaling activation.
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.
authors.affiliation: Authors' Affiliations: Cancer Research Program and.
authors.forename: Neus
authors.initials: N
authors.lastname: Martínez-Bosch
authors.affiliation: Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, Minnesota;
authors.forename: Maite G
authors.initials: MG
authors.lastname: Fernández-Barrena
authors.affiliation: Authors' Affiliations: Cancer Research Program and.
authors.forename: Mireia
authors.initials: M
authors.lastname: Moreno
authors.affiliation: Authors' Affiliations: Cancer Research Program and.
authors.forename: Elena
authors.initials: E
authors.lastname: Ortiz-Zapater
authors.affiliation: Authors' Affiliations: Cancer Research Program and Department of Pathology, IMIM (Hospital del Mar Medical Research Institute), Barcelona;
authors.forename: Jessica
authors.initials: J
authors.lastname: Munné-Collado
authors.affiliation: Authors' Affiliations: Cancer Research Program and Department of Pathology, IMIM (Hospital del Mar Medical Research Institute), Barcelona;
authors.forename: Mar
authors.initials: M
authors.lastname: Iglesias
authors.affiliation: Institut für Physiologische Chemie, Tierärztliche Fakultät, Ludwig-Maximilians-Universität, München, Germany; and.
authors.forename: Sabine
authors.initials: S
authors.lastname: André
authors.affiliation: Institut für Physiologische Chemie, Tierärztliche Fakultät, Ludwig-Maximilians-Universität, München, Germany; and.
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Gabius
authors.affiliation: Department of Surgical Oncology, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas;
authors.forename: Rosa F
authors.initials: RF
authors.lastname: Hwang
authors.affiliation: Institute Jacques Monod, CNRS UMR7592, Université Paris Diderot, Paris, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Poirier
authors.affiliation: Experimental Oncology Group, CNIO, Madrid, Spain;
authors.forename: Carolina
authors.initials: C
authors.lastname: Navas
authors.affiliation: Experimental Oncology Group, CNIO, Madrid, Spain;
authors.forename: Carmen
authors.initials: C
authors.lastname: Guerra
authors.affiliation: Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, Minnesota;
authors.forename: Martin E
authors.initials: ME
authors.lastname: Fernández-Zapico
authors.affiliation: Authors' Affiliations: Cancer Research Program and pnavarro@imim.es.
authors.forename: Pilar
authors.initials: P
authors.lastname: Navarro
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000401:mortality / Q000473:pathology; D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology*; D058405:Desmoplastic Small Round Cell Tumor / Q000235:genetics; D037483:Galectin 1 / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D057809:HEK293 Cells; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009389:Neovascularization, Pathologic / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D034622:RNA Interference; D034741:RNA, Small Interfering
chemical_list: D037483:Galectin 1; D053823:Hedgehog Proteins; C445499:LGALS1 protein, human; D034741:RNA, Small Interfering