ST6GAL1 sialyltransferase promotes acinar to ductal metaplasia and pancreatic cancer progression

Abstract

The role of aberrant glycosylation in pancreatic ductal adenocarcinoma (PDAC) remains an under-investigated area of research. In this study, we determined that the ST6GAL1 sialyltransferase, which adds α2,6-linked sialic acids to N-glycosylated proteins, is upregulated in patients with early-stage PDAC, and further increased in advanced disease. A tumor-promoting function for ST6GAL1 was elucidated using tumor xenograft models with human PDAC cells. Additionally, we developed a genetically-engineered mouse (GEM) with transgenic expression of ST6GAL1 in the pancreas, and found that mice with dual expression of ST6GAL1 and oncogenic KRASG12D have greatly accelerated PDAC progression and mortality compared with mice expressing KRASG12D alone. As ST6GAL1 imparts progenitor-like characteristics, we interrogated ST6GAL1’s role in acinar to ductal metaplasia (ADM), a process that fosters neoplasia by reprogramming acinar cells into ductal, progenitor-like cells. We confirmed that ST6GAL1 promotes ADM using multiple models including the 266-6 cell line, GEM-derived organoids and tissues, and an in vivo model of inflammation-induced ADM. EGFR is a key driver of ADM and is known to be activated by ST6GAL1-mediated sialylation. Importantly, EGFR activation was dramatically increased in acinar cells and organoids from mice with transgenic ST6GAL1 expression. These collective results highlight a novel glycosylation-dependent mechanism involved in early stages of pancreatic neoplasia.

High-Throughput Analysis Reveals miRNA Upregulating α-2,6-Sialic Acid through Direct miRNA–mRNA Interactions

“…Interestingly, the up-miR, miR-221-5p, which has a strong impact on ST6GAL1 and α-2,6-sialylation, is highly expressed in pancreatic cancer and is associated with decreased survival . In recent work, ST6GAL1 and α-2,6-sialylation have also been shown to be important in pancreatic cancer formation and progression and correlate with decreased survival. ,, This points toward a potential functional role for upregulatory miRNA in controlling cancer-related protein and glycan expression.…”

“… 34 In recent work, ST6GAL1 and α-2,6-sialylation have also been shown to be important in pancreatic cancer formation and progression and correlate with decreased survival. 5 , 6 , 38 This points toward a potential functional role for upregulatory miRNA in controlling cancer-related protein and glycan expression.…”

“…Chemical biology tools have increasingly revealed the importance of sialic acids as a major signal in physiology and disease. − α-2,6-Linked sialic acids on galactose drive cancer development and metastasis, − immunological recognition, − and microglial phagocytosis. , This modification is biosynthesized by two enzymes: ST6-β-galactoside-α-2,6-sialyltranferase-1 (ST6GAL1), expressed throughout the human body, and ST6GAL2, predominantly seen in brain, breast, and colon (Figure ). , Although this modification is critical in both health and disease, the regulation and dysregulation of these enzymes and thus α-2,6-linked sialic acid are poorly understood.…”

ST6Gal1: Oncogenic signaling pathways and targets

“…Elevated Wnt signaling, including via increased expression of regulators like WNT3A and β-catenin, was identified in RNAsequencing analysis of metastatic subclones of pancreatic cancer cell lines S2-LM7AA and S2-013 that expressed high levels of ST6Gal1 (Britain et al, 2021). This finding was recently corroborated with RNA-sequencing analysis of the pancreas from GEMM models with pancreas-specific ST6Gal1 overexpression (Chakraborty et al, 2022): these data showed elevated stem cell-related pathways including Wnt (Chakraborty et al, 2022). Furthermore, elevated levels of ST6Gal1 in the colorectal cancer cell lines Caco-2 and SW48 were associated with increased expression of WNT3a and β-catenin as well as fluorouracil (5-FU) resistance (Cui et al, 2018).…”

“…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). Considering RAS mutations are observed in up to 93% of pancreatic cancer patients, the results of these studies strongly suggest ST6Gal1 as a downstream mediator of, and potential therapeutic target in, RASmediated pancreatic oncogenesis.…”