Targeting hypersialylation in pancreatic cancer microfluidic models reverses its malignant phenotype and enhances CAR-T therapy

Abstract Pancreatic ductal adenocarcinoma (PDA) exhibits extensive hypersialylation, a glycosylation hallmark associated with tumor progression and immune evasion. Here, we employed physiologically relevant 3D microfluidic models, which mimic key aspects of the tumor microenvironment, to evaluate the impact of sialyltransferase inhibition using the sialic acid analog Ac 5 3F ax Neu5Ac in PDA cell models. This glycomimetic compound reduced α2,3-sialylation without compromising cell viability in self-organized PDA spheroids. Desialylation decreased the number and velocity of migrating cells in confined and unconfined microenvironments, and reduced cell adhesion to engineered endothelial vessels, consistent with reduced metastatic ability. Notably, 3D co-culture with CAR-T cells revealed enhanced T cell-mediated cytotoxicity upon sialylation inhibition, leading to reduced spheroid size and viability. Collectively, this work provides new insights into the role of sialylation in modulating tumor morphology, cell viability, migratory behavior, and interactions with immune effector cells, underscoring the value of biomimetic microfluidic models for evaluation of anti-metastatic strategies. Overall, targeting hypersialylation reprograms the malignant phenotype of PDA and may enhance immunotherapeutic efficacy, supporting the development of glycan-targeting strategies in cancer therapy.

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Publication Details

Journal
Cell Death and Disease
Published
2026-11-02
DOI
https://doi.org/10.1038/s41419-026-09354-0
Primary Topic
Glycosylation and Glycoproteins Research
Type
article
Field-Weighted Citation Impact
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article

Targeting hypersialylation in pancreatic cancer microfluidic models reverses its malignant phenotype and enhances CAR-T therapy

María José Gómez‐Benito, Julián Pardo, William J. Polacheck, José Manuel García‐Aznar et al.
2 links
Cell Death and Disease
Glycosylation and Glycoproteins Research
article

Targeting hypersialylation in pancreatic cancer microfluidic models reverses its malignant phenotype and enhances CAR-T therapy

María José Gómez‐Benito, Julián Pardo, William J. Polacheck, José Manuel García‐Aznar, Diego Sánchez‐Martínez, Júlia López, Patricia Balsas, Rosa Peracaula, Esther Llop, Pedro Enrique Guerrero, Laura Miró, Soraya Hernández-Hatibi, Jack Zhang-Zhou, Maria del Valle Blazquez-Romero, Alejandro Martín-Contreras
article en

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDA) exhibits extensive hypersialylation, a glycosylation hallmark associated with tumor progression and immune evasion. Here, we employed physiologically relevant 3D microfluidic models, which mimic key aspects of the tumor microenvironment, to evaluate the impact of sialyltransferase inhibition using the sialic acid analog Ac 5 3F ax Neu5Ac in PDA cell models. This glycomimetic compound reduced α2,3-sialylation without compromising cell viability in self-organized PDA spheroids. Desialylation decreased the number and velocity of migrating cells in confined and unconfined microenvironments, and reduced cell adhesion to engineered endothelial vessels, consistent with reduced metastatic ability. Notably, 3D co-culture with CAR-T cells revealed enhanced T cell-mediated cytotoxicity upon sialylation inhibition, leading to reduced spheroid size and viability. Collectively, this work provides new insights into the role of sialylation in modulating tumor morphology, cell viability, migratory behavior, and interactions with immune effector cells, underscoring the value of biomimetic microfluidic models for evaluation of anti-metastatic strategies. Overall, targeting hypersialylation reprograms the malignant phenotype of PDA and may enhance immunotherapeutic efficacy, supporting the development of glycan-targeting strategies in cancer therapy.

Cell Death and Disease
University of North Carolina at Chapel Hill (US), North Carolina State University (US), Universitat de Girona (ES), Universidad de Zaragoza (ES), Instituto de Salud Carlos III (ES), Fundacion Agencia Aragonesa para la Investigacion y el Desarrollo (ES), Centro de Investigación Biomédica en Red (ES), Instituto de Investigación Sanitaria Aragón (ES), Instituto de Investigación en Ingeniería de Aragón (ES), Centro de Investigación Biomédica en Red Enfermedades Infecciosas (ES)
Good health and well-being
Openalex Percentile: Top 25%
Glycosylation and Glycoproteins Research
DOIOpen Access PDFOpenAlex
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