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Aberrant Glycosylation Promotes Pancreatic Inflammation

ABSTRACT: CA19-9 is a glycan elevated in human gastrointestinal pathologies, but absent from rodents. We humanized the mouse glycome and found that CA19-9 is not only a correlative biomarker of pancreatic disease, but also plays a causative role in the initiation of pancreatitis. Elevation of CA19-9 results in the activation of EGFR signaling in the normal pancreatic ductal compartment through secretion of Fibulin 3. These signaling changes can be blocked by blocking either CA19-9 or Fibulin 3.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

SUBMITTER: Keith Rivera

LAB HEAD: David Tuveson

PROVIDER: PXD008564 | Pride | 2019-06-06

REPOSITORIES: Pride

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Project description:Background & Aims: Perturbations in pancreatic ductal bicarbonate secretion often result in chronic pancreatitis. Although the physiological mechanism of ductal secretion is known, its transcriptional control is not well characterized. Here, we investigate the role of the transcription factor Hematopoietically-expressed homeobox protein (Hhex) in pancreatic secretion and pancreatitis. Methods: We derived mice with pancreas-specific, Cre-mediated Hhex gene ablation to determine the requirement of Hhex in the pancreatic duct in early life and in adult stages. Histological and immunostaining analyses were used to detect the presence of pathology. Pancreatic primary ductal cells (PDCs) were isolated to discover differentially expressed transcripts upon acute Hhex ablation. Results: Hhex protein was detected throughout the embryonic and adult ductal trees. Ablation of Hhex in pancreatic progenitors resulted in postnatal ductal ectasia associated with acinar-to-ductal metaplasia, a progressive phenotype that ultimately resulted in chronic pancreatitis. Hhex ablation in adult mice, however, did not cause any detectable pathology. Ductal ectasia did not result from perturbations in primary cilia, but was consistent with the effects of primary ductal hypertension. RNA-seq analysis of Hhex-ablated PDCs indicated the G-protein coupled receptor Natriuretic peptide receptor 3, implicated in paracrine signaling, was upregulated 4.70-fold. Conclusions: Although Hhex is dispensable for adult pancreatic function, ablation of Hhex in pancreatic progenitors results in profound pancreatitis that is consistent with primary ductal hypertension. Our data highlight the critical role of paracrine signaling in maintaining ductal homeostasis, especially in early life, and support ductal hypersecretion as a novel etiology of pediatric chronic pancreatitis. Pancreatic primary ductal cells (PDCs) were isolated from uninduced adult HhexL/L;Sox9CreERT2 (n=2) and littermate control HhexL/L (n=2) mice. PDCs were treated with 500nM 4-hydroxytamoxifen in vitro for 4 days, and then RNA was collected for transcriptome analysis.

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	8plex1_Fx1.raw	Raw
	8plex1_Fx2.raw	Raw
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	8plex1_Fx4.raw	Raw

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Aberrant Glycosylation Promotes Pancreatic Inflammation

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