Sialyltransferase inhibitor Ac53FaxNeu5Ac reverts the malignant phenotype of pancreatic cancer cells, and reduces tumor volume and favors T-cell infiltrates in mice

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• dc.contributor.author Miró, Laura
• dc.contributor.author López, Júlia
• dc.contributor.author Guerrero, Pedro E.
• dc.contributor.author Martínez Bosch, Neus
• dc.contributor.author Manero Rupérez, Noemí
• dc.contributor.author Moreno, Mireia
• dc.contributor.author Ortiz, María Rosa
• dc.contributor.author Llop Escorihuela, Esther
• dc.contributor.author Navarro Medrano, Pilar
• dc.contributor.author Peracaula, Rosa
• dc.date.accessioned 2023-03-01T07:29:35Z
• dc.date.available 2023-03-01T07:29:35Z
• dc.date.issued 2022
• dc.description.abstract Hypersialylation is a feature of pancreatic ductal adenocarcinoma (PDA) and it has been related to tumor malignancy and immune suppression. In this work, we have evaluated the potential of the sialyltransferase inhibitor, Ac53FaxNeu5Ac, to decrease tumor sialoglycans in PDA and to revert its malignant phenotype. Sialoglycans on PDA cells were evaluated by flow cytometry, and the functional impact of Ac53FaxNeu5Ac was assessed using E-selectin adhesion, migration, and invasion assays. PDA tumors were generated in syngeneic mice from KC cells and treated with Ac53FaxNeu5Ac to evaluate tumor growth, mice survival, and its impact on blocking sialic acid (SA) and on the tumor immune component. Ac53FaxNeu5Ac treatment on human PDA cells decreased α2,3-SA and sialyl-Lewisx, which resulted in a reduction in their E-selectin adhesion, and in their migratory and invasive capabilities. Subcutaneous murine tumors treated with Ac53FaxNeu5Ac reduced their volume, their SA expression, and modified their immune component, with an increase in CD8+ T-lymphocytes and NK cells. In conclusion, Ac53FaxNeu5Ac treatment weakened PDA cells' malignant phenotype, thereby reducing tumor growth while favoring anti-tumor immune surveillance. Altogether, these results show the positive impact of reducing SA expression by inhibiting cell sialyltransferases and open the way to use sialyltransferase inhibitors to target this dismal disease.
• dc.description.sponsorship This research was funded by Spanish Ministry of Science and Innovation (grant PID2020-115686RB-I00) and University of Girona (PONT2019/20- and PONT2020/04) to R.P., and MICINN-FIS PI20/00625 to P.N.
• dc.format.mimetype application/pdf
• dc.identifier.citation Miró L, López J, Guerrero PE, Martínez-Bosch N, Manero-Rupérez N, Moreno M, et al. Sialyltransferase inhibitor Ac53FaxNeu5Ac reverts the malignant phenotype of pancreatic cancer cells, and reduces tumor volume and favors T-cell infiltrates in mice. Cancers (Basel). 2022 Dec 12; 14 (24): 6133. DOI: 10.3390/cancers14246133
• dc.identifier.doi http://dx.doi.org/10.3390/cancers14246133
• dc.identifier.issn 2072-6694
• dc.identifier.uri http://hdl.handle.net/10230/55985
• dc.language.iso eng
• dc.publisher MDPI
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2020-115686RB-I00
• dc.rights Copyright © 2022 by Miró L, López J, Guerrero PE, Martínez-Bosch N, Manero-Rupérez N, Moreno M, et al. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword E-selectin adhesion
• dc.subject.keyword Immune component
• dc.subject.keyword Invasion
• dc.subject.keyword Pancreatic cancer
• dc.subject.keyword Sialic acid
• dc.subject.keyword Sialyl-Lewis x
• dc.subject.keyword Sialyltransferase inhibitor
• dc.subject.keyword Syngeneic mice
• dc.title Sialyltransferase inhibitor Ac53FaxNeu5Ac reverts the malignant phenotype of pancreatic cancer cells, and reduces tumor volume and favors T-cell infiltrates in mice
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion