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
| PRJNA541770 | ENA
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
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| 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: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
Project description:Pancreatic duct organoids have emerged as a valuable tool for investigating pancreas biology and physiology through in vitro modeling. Despite their widespread use, a comprehensive understanding of the cellular heterogeneity of organoids and their underlying tissue remains elusive. Here we performed single-cell transcriptomic profiling of human adult pancreatic exocrine tissue and their derived organoids, revealing a gradient of keratin expression within the ductal network that clustered cells into two distinct low- and high-keratin subpopulations. Keratin-high cells display a higher capacity to form organoids while keratin-low cells express stemness associated markers. Finally, comparative gene expression analysis between ductal tissue and derived organoids revealed a partial recapitulation of the in vivo heterogeneity. These findings further our knowledge on pancreatic duct organoids and pave the way for future investigations into the heterogeneity of the pancreatic ductal syste
2024-04-09 | GSE263364 | GEO
Project description:To determine the molecular basis of gene regulation in pancreatic ductal epithelial cells, we developed methods for the isolation of this cell population during mouse development and normal adult homeostasis, as well as in conditions with ductal features (acinar-to-ductal metaplasia (ADM), pancreatic intraepithelial neoplasia (PanIN) and pancreatic ductal adenocarcinoma (PDAC)). Our technique utilizes the specificity of Dolichos biflorus Agglutinin (DBA) lectin marking the entire normal ductal tree, including terminal intercalated ducts (putative sites of stem or progenitor cells) and ductal structures in ADM and PanIN. We used ferromagnetic-labeled DBA lectin to isolate ductal structures. Ductal cells were isolated under the following conditions: (1) Embryonic Development in wild type mice: E14.5, E15.5, E16.5, and postnatal day 1 (P1); (2) Injury and regeneration (pancreatitis) 0, 1, 3, 5 days following cerulein-induced acute pancreatitis. Cerulein is a cholecystokinin analog which produces a self-limited pancreatitis with injury and subsequent regeneration and repair, completed five days after insult; and (3) Pdx1-Cre;LSL-KrasG12D/+ mice aged 10 and 20 weeks that harbor PanIN lesions and a subset develop PDAC. Ductal/PanIN cells were isolated from these mice and appropriate control mice (Pdx1-Cre;Kras+/+).
2015-09-30 | GSE40895 | GEO