The Glycan CA19-9 Promotes Pancreatitis and Pancreatic Cancer In Mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE130854 | GEO | 2019/06/05
REPOSITORIES: GEO
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Project description:The Glycan CA19-9 Promotes Pancreatitis and Pancreatic Cancer In Mice
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Project description:A subset of pancreatic ductal adenocarcinomas (PDACs) is highly resistant to systemic chemotherapy, but no markers are available in clinical settings to identify this subset. We found that chemotherapy-resistant PDACs, but not chemotherapy-sensitive PDACs, express a glycan biomarker called sTRA. We confirmed the use of this marker to identify treatment-resistant PDAC in multiple systems: sets of 24 cell lines, 27 organoids, and isogenic cell lines; gene-expression signatures in primary tumors; tissue microarrays containing primary tumors; and blood plasma from cohorts of human subjects. These findings establish the use of tissue or plasma assays to identify the PDACs that are resistant to chemotherapy, which could improve the precision of systemic treatments and facilitate biomarker-guided trials targeting resistant PDAC.
2021-04-13 | GSE146722 | GEO
Project description:Glycosylation alterations are indicative of tissue inflammation and neoplasia, but whether these alterations contribute to disease pathogenesis is largely unknown. To study the role of glycan changes in pancreatic disease, we inducibly expressed human fucosyltransferase 3 and ?1,3-galactosyltransferase 5 in mice, reconstituting the glycan sialyl-Lewisa, also known as carbohydrate antigen 19-9 (CA19-9). Notably, CA19-9 expression in mice resulted in rapid and severe pancreatitis with hyperactivation of epidermal growth factor receptor (EGFR) signaling. Mechanistically, CA19-9 modification of the matricellular protein fibulin-3 increased its interaction with EGFR, and blockade of fibulin-3, EGFR ligands, or CA19-9 prevented EGFR hyperactivation in organoids. CA19-9-mediated pancreatitis was reversible and could be suppressed with CA19-9 antibodies. CA19-9 also cooperated with the KrasG12D oncogene to produce aggressive pancreatic cancer. These findings implicate CA19-9 in the etiology of pancreatitis and pancreatic cancer and nominate CA19-9 as a therapeutic target.
| S-EPMC6705393 | biostudies-literature
Project description: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.
2019-06-06 | PXD008564 | Pride
Project description:We investigated transcriptomic changes in pancreatic ductal organoids under adaptation to an acidic extracellular environment.
2024-06-04 | GSE218173 | GEO
Project description:We investigated transcriptomic changes in PanIN ("mP4") mouse pancreatic ductal organoids under acute or long-term treatment of Gemcitabine and Erlotinib.
2024-06-04 | GSE218177 | GEO
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.
2015-11-20 | E-GEOD-63526 | biostudies-arrayexpress
Project description:To investigate pancreatic, ductal CFTR function, organoids from porcine pancreas were cultured. RNA was extracted from pancreatic organoids at passage 3 and 5 after organoid establishment.
2024-01-18 | GSE233579 | GEO
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.
2015-11-20 | GSE63526 | GEO
Project description:Full protein measurements from in vitro differentiation of the human embryonic stem cell line HUES8 into pancreatic progenitors (PP) and pancreatic duct-like organoids (PDLOs). Protein intensities were quantified by mass spectrometry analysis from PPs at day 13 and from PDLOs at day 59. Please see related publication “Modelling Plasticity and Dysplasia of Pancreatic Ductal Organoids Derived from Human Pluripotent Stem Cells” for experimental details.
2021-03-19 | PXD018785 | Pride