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

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 analysis 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.

Multivalent DNA-encoded lectins on phage enable detecting compositional glycocalyx differences

“…LiLA, like other versions of lectin arrays, fluorescent lectins and mass cytometry, offers the powerful capacity to understand the composition of glycocalyx. Differences on glycocalyx composition between normal and cancer cells as well as invading pathogens have been studied by slide-based lectin arrays [53][54][55][56] . LiLA adds a previously untapped ability to measure the composition of glycocalyx on intact cells in complex cellular mixtures, and in an animal model.…”

ST6Gal1: Oncogenic signaling pathways and targets

“…Furthermore, in a Genetically Engineered Mouse Model (GEMM) of pancreatic cancer with RAS activation via expression of K-Ras G12D under the control of p48Cre (Qian et al, 2009), the loss of ST6Gal1 resulted in normal acinar area and decreased fibrosis (Kurz et al, 2021). This led to delayed disease development and progression (Kurz et al, 2021). Corroborating these findings, in pancreatic organoids developed from mice expressing K-Ras G12D under the control of Pdx1-Cre, knockdown of ST6Gal1 inhibited organoid growth (Chakraborty et al, 2022).…”

“…Using 63 melanoma cell lines, ST6Gal1 was identified by Johansson et al as a gene that was consistently upregulated with activating BRAF mutation (Johansson et al, 2007). Furthermore, in a Genetically Engineered Mouse Model (GEMM) of pancreatic cancer with RAS activation via expression of K-Ras G12D under the control of p48Cre (Qian et al, 2009), the loss of ST6Gal1 resulted in normal acinar area and decreased fibrosis (Kurz et al, 2021). This led to delayed disease development and progression (Kurz et al, 2021).…”