ST6GAL1 sialyltransferase promotes acinar to ductal metaplasia and pancreatic cancer progression
Nikita Bhalerao, Asmi Chakraborty, Michael P. Marciel, Jihye Hwang, Colleen M. Britain, Austin D. Silva, Isam E. Eltoum, Robert B. Jones, Katie L. Alexander, Lesley E. Smythies, Phillip D. Smith, David K. Crossman, Michael R. Crowley, Boyoung Shin, Laurie E. Harrington, Zhaoqi Yan, Maigen M. Bethea, Chad S. Hunter, Christopher A. Klug, Donald J. Buchsbaum, Susan L. Bellis
Nikita Bhalerao, Asmi Chakraborty, Michael P. Marciel, Jihye Hwang, Colleen M. Britain, Austin D. Silva, Isam E. Eltoum, Robert B. Jones, Katie L. Alexander, Lesley E. Smythies, Phillip D. Smith, David K. Crossman, Michael R. Crowley, Boyoung Shin, Laurie E. Harrington, Zhaoqi Yan, Maigen M. Bethea, Chad S. Hunter, Christopher A. Klug, Donald J. Buchsbaum, Susan L. Bellis
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Research Article Oncology

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 ST6 β-galactoside α2,6 sialyltransferase 1 (ST6GAL1), which adds α2,6-linked sialic acids to N-glycosylated proteins, was upregulated in patients with early-stage PDAC and was further increased in advanced disease. A tumor-promoting function for ST6GAL1 was elucidated using tumor xenograft experiments with human PDAC cells. Additionally, we developed a genetically engineered mouse (GEM) model with transgenic expression of ST6GAL1 in the pancreas and found that mice with dual expression of ST6GAL1 and oncogenic KRASG12D had greatly accelerated PDAC progression 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 verified 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 glycosylation-dependent mechanism involved in early stages of pancreatic neoplasia.

Authors

Nikita Bhalerao, Asmi Chakraborty, Michael P. Marciel, Jihye Hwang, Colleen M. Britain, Austin D. Silva, Isam E. Eltoum, Robert B. Jones, Katie L. Alexander, Lesley E. Smythies, Phillip D. Smith, David K. Crossman, Michael R. Crowley, Boyoung Shin, Laurie E. Harrington, Zhaoqi Yan, Maigen M. Bethea, Chad S. Hunter, Christopher A. Klug, Donald J. Buchsbaum, Susan L. Bellis

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Figure 3

RNA-Seq of GEM pancreata reveals that ST6GAL1 promotes a stem and ductal phenotype and enhances activation of EGFR and other ERBB family members.

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RNA-Seq of GEM pancreata reveals that ST6GAL1 promotes a stem and ductal...
(A) Ingenuity Pathway Analysis (IPA) of RNA-Seq data from 20-week-old SC and WT pancreata. The 5 top-scoring IPA networks altered in SC versus WT mice are shown (n = 3 mice/genotype). (B) GSEA indicates that compared with WT mice, SC mice have an upregulation in stemness networks (ESC pluripotency, Notch, Wnt, Hedgehog) as well as networks associated with a pancreatic ductal cell program and pancreatic cancer. NES and FDR values are as follows: ESC pluripotency: NES = 2.04, FDR = 0.011; Wnt: NES = 1.48, FDR = 0.103; Notch: NES = 1.70, FDR = 0.008; Hedgehog: NES = 1.89, FDR = 0.003; ductal: NES = 1.59, FDR = 0.018; pancreatic cancer: NES = 1.44, FDR = 0.135. NES, normalized enrichment score. (C) Heatmap of select genes from the pancreatic ductal network upregulated in SC mice (n = 3 mice/genotype). (D) GSEA reveals activation of EGFR and other receptor tyrosine kinases in SC mice. EGFR: NES = 2.22, FDR = 0.003; ERBB family: NES = 1.96, FDR = 0.015; ERBB2: NES = 1.96, FDR = 0.049; ERBB4: NES = 1.78, FDR = 0.023; MET: NES = 2.04, FDR = 0.010. (E) IPA of RNA-Seq data from 20-week-old KSC and KC pancreata depicting the 5 top-scoring IPA networks (n = 3 mice/genotype). (F) GSEA indicates that compared with KC mice, KSC mice have an upregulation in stemness-associated networks (ESC pluripotency, Notch, Wnt, and Hedgehog) and networks associated with a ductal phenotype and pancreatic cancer. NES and FDR values are as follows: ESC pluripotency: NES = 1.84, FDR = 0.033; Wnt: NES = 1.49, FDR = 0.123; Notch: NES = 1.38, FDR = 0.077; Hedgehog: NES = 2.09, FDR < 0.0005; ductal: NES = 1.65, FDR = 0.019; pancreatic cancer: NES = 1.26, FDR = 0.280.