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Orozco, Carlos A.; Martinez-Bosch, Neus; Guerrero, Pedro E.; Vinaixa, Judith; Dalotto-Moreno, Tomas; Iglesias, Mar; Moreno, Mireia; Djurec, Magdolna; Poirier, Francoise; Gabius, Hans-Joachim; Fernandez-Zapico, Martin E.; Hwang, Rosa F.; Guerra, Carmen; Rabinovich, Gabriel A. and Navarro, Pilar (2018): Targeting galectin-1 inhibits pancreatic cancer progression by modulating tumor-stroma crosstalk. In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, No. 16, E3769-E3778

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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.

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