Targeting galectin-1 inhibits pancreatic cancer progression by modulating tumor-stroma crosstalk

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.CKNOWLEDGMENTS. We thank J. M. Caballero (PRBB Animal Facility) and the staffs of the UPF Flow Cytometry and the IMIM microarray core facilities for helpful technical assistance, Raul Peña and the Epithelial-to-Mesenchymal Transition and Cancer Progression group (IMIM) for providing reagents and valuable technical help, and V. A. Raker for English proofreading and manu- script editing. Images for figure preparation were provided by SMART (Servier Medical Art, https://smart.servier.com/ ). This work was supported by Spanish Ministry of Economy and Competitiveness/ISCIII-FEDER Grants PI14/00125 and PI17/00199, the Carmen Delgado/Miguel Pérez-Mateo Asociación Española de Pancreatología/ Asociación Cáncer de Páncreas 2016 Grant, and Generalitat de Catalunya Grant 2014/SGR/143 (to P.N.). M.E.F.-Z. was supported by Mayo Clinic Pancreatic Specialized Program of Research Excellence Grant P50 CA102701 and Mayo Clinic Center for Cell Signaling in Gastroenterology Grant P30 DK84567. C.A.O. was supported by the International PhD Studies Fellowship Créditos Beca Francisco José de Caldas from the Colombian Administrative Department of Science, Technology and Innovation (Colciencias). M.D. was supported by a fellowship from La Caixa International Fellowship Program. G.A.R. was supported by Argentinean Agency for Promotion of Science and Technology Grant PICT 2014-3687 and by grants from the University of Buenos Aires, the Sales Foundation, and the Bunge and Born Foundation. T.D.-M. is a postdoctoral fellow supported by the Argentine National Scientific and Tech- nical Research CouncilS