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Integrated Systems-Analysis of the Human and Murine Pancreatic Cancer Glycomes Reveal a Tumor Promoting Role for ST6GAL1

Emma Kurz, Shuhui Chen, Emily Vucic, Gillian Baptiste, Cynthia Loomis, Praveen Agarwal, Cristina Hajdu, Dafna Bar-Sagi, Lara K. Mahal
doi: https://doi.org/10.1101/2021.03.10.434864
Emma Kurz
1Department of Cell Biology, NYU Grossman School of Medicine, New York, NY
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Shuhui Chen
2Biomedical Research Institute, Department of Chemistry, New York University, New York, NY
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Emily Vucic
3Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY
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Gillian Baptiste
4Department of Pathology, NYU Grossman School of Medicine, New York, NY
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Cynthia Loomis
5Office of Science and Research, NYU Grossman School of Medicine, New York, NY
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Praveen Agarwal
4Department of Pathology, NYU Grossman School of Medicine, New York, NY
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Cristina Hajdu
4Department of Pathology, NYU Grossman School of Medicine, New York, NY
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Dafna Bar-Sagi
3Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY
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  • For correspondence: lkmahal@ualberta.ca Dafna.Bar-Sagi@nyulangone.org
Lara K. Mahal
2Biomedical Research Institute, Department of Chemistry, New York University, New York, NY
6Department of Chemistry, University of Alberta, Edmonton, AB, Canada
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  • For correspondence: lkmahal@ualberta.ca Dafna.Bar-Sagi@nyulangone.org
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ABSTRACT

Pancreatic ductal adenocarcinoma (PDA) is the 3rd leading cause of cancer-death in the U.S.. Glycans, such as CA-19-9, are biomarkers of PDA and are emerging as important modulators of cancer phenotypes. Herein, we utilized a systems-based approach integrating glycomic analysis of human PDA and the well-established KC mouse model, with transcriptomic data to identify and probe the functional significance of aberrant glycosylation in pancreatic cancer. We observed both common and distinct patterns of glycosylation in pancreatic cancer across species. Common alterations included increased levels of α-2,3- and α-2,6-sialic acids, bisecting GlcNAc and poly-LacNAc. However, core fucose, which was increased in human PDAC, was not seen in the mouse, indicating that not all human glycomic changes can be modeled in the KC mouse. In silico a nalysis of bulk and single cell sequencing data identified ST6GAL1, which underlies α-2,6-sialic acid, as overexpressed in human PDA, concordant with histological data. Enzymes levels correlated with the stage of clinical disease. To test whether ST6GAL1 promotes pancreatic cancer we created a novel mouse in which a pancreas-specific genetic deletion of this enzyme overlays the KC mouse model. Analysis of our new model showed delayed cancer formation and a significant reduction in fibrosis. Our results highlight the importance of a strategic systems-approach to identifying glycans whose functions can be modeled in mouse, a crucial step in the development of therapeutics targeting glycosylation in pancreatic cancer.

SIGNIFICANCE Pancreatic ductal adenocarcinoma (PDA) is the 3rd leading cause of cancer-death in the U.S.. Glycosylation is emerging as an important modulator of cancer phenotype. Herein we use a systems-approach integrating glycomics of human PDA and a well-established PDA mouse model with transcriptomic data to identify ST6GAL1, the enzyme underlying α-2,6-sialic acid, as a potential cancer promoter. A pancreatic specific ST6GAL1 knockout in the KC mouse showed delayed cancer formation and a reduction in fibrosis. Our results highlight the importance of a strategic systems-approach to identifying glycans whose functions can be modeled in mouse, a crucial step in the development of therapeutics targeting glycosylation in pancreatic cancer.

Competing Interest Statement

The authors have declared no competing interest.

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Posted March 10, 2021.
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Integrated Systems-Analysis of the Human and Murine Pancreatic Cancer Glycomes Reveal a Tumor Promoting Role for ST6GAL1
Emma Kurz, Shuhui Chen, Emily Vucic, Gillian Baptiste, Cynthia Loomis, Praveen Agarwal, Cristina Hajdu, Dafna Bar-Sagi, Lara K. Mahal
bioRxiv 2021.03.10.434864; doi: https://doi.org/10.1101/2021.03.10.434864
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Integrated Systems-Analysis of the Human and Murine Pancreatic Cancer Glycomes Reveal a Tumor Promoting Role for ST6GAL1
Emma Kurz, Shuhui Chen, Emily Vucic, Gillian Baptiste, Cynthia Loomis, Praveen Agarwal, Cristina Hajdu, Dafna Bar-Sagi, Lara K. Mahal
bioRxiv 2021.03.10.434864; doi: https://doi.org/10.1101/2021.03.10.434864

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