Sialyltransferase Inhibitor Ac53FaxNeu5Ac Reverts the Malignant Phenotype of Pancreatic Cancer Cells, and Reduces Tumor Volume and Favors T-Cell Infiltrates in Mice

Laura Miró; Júlia López; Pedro E Guerrero; Neus Martínez-Bosch; Noemí Manero-Rupérez; Mireia Moreno; M Rosa Ortiz; Esther Llop; Pilar Navarro; Rosa Peracaula

doi:10.3390/cancers14246133

Sialyltransferase Inhibitor Ac₅3F_axNeu5Ac 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.

Authors

Laura Miró^{1

2}, Júlia López^{1

2}, Pedro E Guerrero^{1

2}, Neus Martínez-Bosch³, Noemí Manero-Rupérez³, Mireia Moreno³, M Rosa Ortiz⁴, Esther Llop^{1

2}, Pilar Navarro^{3

5

6}, Rosa Peracaula^{1

2}

Affiliations

¹ Biochemistry and Molecular Biology Unit, Department of Biology, University of Girona, 17003 Girona, Spain.
² Girona Biomedical Research Institute (IDIBGI), 17190 Girona, Spain.
³ Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM), Unidad Asociada IIBB-CSIC, 08003 Barcelona, Spain.
⁴ Pathology Department, Josep Trueta University Hospital, 17007 Girona, Spain.
⁵ Institute of Biomedical Research of Barcelona (IIBB)-CSIC, 08036 Barcelona, Spain.
⁶ Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain.

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, Ac₅3F_axNeu5Ac, 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 Ac₅3F_axNeu5Ac was assessed using E-selectin adhesion, migration, and invasion assays. PDA tumors were generated in syngeneic mice from KC cells and treated with Ac₅3F_axNeu5Ac to evaluate tumor growth, mice survival, and its impact on blocking sialic acid (SA) and on the tumor immune component. Ac₅3F_axNeu5Ac treatment on human PDA cells decreased α2,3-SA and sialyl-Lewis^x, which resulted in a reduction in their E-selectin adhesion, and in their migratory and invasive capabilities. Subcutaneous murine tumors treated with Ac₅3F_axNeu5Ac reduced their volume, their SA expression, and modified their immune component, with an increase in CD8⁺ T-lymphocytes and NK cells. In conclusion, Ac₅3F_axNeu5Ac 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.

Keywords: E-selectin adhesion; immune component; invasion; pancreatic cancer; sialic acid; sialyl-Lewis x; sialyltransferase inhibitor; syngeneic mice.

Abstract

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