Mus musculus
Ontology highlight
ABSTRACT:
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| DRR099096.fastq.gz | Fastqsanger.gz | |||
| DRR099097.fastq.gz | Fastqsanger.gz | |||
| DRR099098.fastq.gz | Fastqsanger.gz | |||
| DRR099099.fastq.gz | Fastqsanger.gz | |||
| DRR099100.fastq.gz | Fastqsanger.gz |
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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
Project description:Background & Aims Pancreatitis is an inflammatory disease of the exocrine pancreas and a known risk factor for pancreatic ductal adenocarcinoma (PDAC). Previously, we identified HMG- box transcription factor 1 (HBP1) as a potential master transcription factor (TF) in the early progression of PDAC, with its expression associated with poor patient survival, underscoring its significance in pancreatic disease. However, the functional role of HBP1 in the onset and progression of acute pancreatitis (AP) remains unknown. Methods We examined HBP1 expression in human pancreatitis samples and a cerulein-induced AP mouse model. Pancreatic-specific conditional HBP1 knockout mice, with or without an oncogenic Kras mutation, were generated and compared to their littermate controls. Spatial transcriptomics and multiplexed protein assays, histological analysis, and immunostaining were utilized to characterize pathological changes. Findings from mouse models were validated using inducible HBP1-overexpressing human pancreatic ductal epithelial cells. Results HBP1 was upregulated in pancreatic exocrine cells in human chronic pancreatitis and mouse acute pancreatitis, with its expression in human chronic pancreatitis correlating with cancer presence. Pancreatic HBP1 ablation disrupted acinar homeostasis by impairing autophagic flux and exacerbating inflammation following injury. In the presence of oncogenic KRAS, HBP1 ablation delayed the formation of pancreatic intraepithelial neoplasia (PanIN), the precursor to PDAC, and slowed its progression to higher-grade lesions. Conclusions HBP1 upregulation in pancreatitis mitigates pancreatic inflammatory injury; however, in the presence of oncogenic KRAS, it facilitates PanIN progression. Thus, HBP1 serves as a critical regulator in both pancreatitis and early pancreatic neoplasia, representing a potential therapeutic target for intervening pancreatitis and PanIN progression.
2025-07-16 | GSE296582 | GEO
Project description:We used single-cell RNA sequencing to profile mouse pancreas across models of acute pancreatitis (AP), recurrent acute pancreatitis (RAP), chronic pancreatitis (CP), and oncogenic Kras-driven acute pancreatitis (K-AP, abbreviated APK). We captured both whole-pancreas cell suspensions and FACS-enriched mKate2+ epithelial populations from defined timepoints spanning early injury, recurrent damage, chronic inflammation, and Kras-driven precursor lesion formation. These data characterize acinar and epithelial plasticity and associated microenvironmental remodeling across pancreatitis and Kras-mediated disease initiation. BACKGROUND & AIMS: In response to injury, pancreatic acinar cells undergo acinar-to-ductal metaplasia (ADM), marked by loss of acinar identity and acquisition of ductal features. While ADM can resolve to support tissue repair, it may also persist and serve as a precursor to pancreatic cancer. Whether diverse pancreatic stressors drive a shared or context-specific ADM program remains unclear. We sought to comprehensively define metaplastic responses to clinically relevant exocrine pancreas diseases known to increase cancer risk. METHODS: We profiled ADM and the surrounding microenvironment across mouse models of exocrine disease—including acute, recurrent, and chronic pancreatitis, as well as in the setting of oncogenic Kras—capturing over 300,000 single cells. To enable high-quality transcriptomic profiling in enzyme-rich tissue, we leveraged FixNCut, a method that preserves RNA integrity in the exocrine pancreas. Findings were validated in human pancreas tissue using CosMx spatial transcriptomics. RESULTS: We identify a conserved acinar response across disease contexts that gives rise to previously unrecognized distinct metaplastic states, including a “gateway” ADM population that precedes more advanced metaplastic states marked by complete loss of acinar identity. In pancreatic intraepithelial neoplasia (PanIN) precancerous lesions, we detect classical-like and basal-like states, suggesting that pancreatic cancer subtypes are specified much earlier than previously appreciated. In Kras-mutant tissue, we identify a second wave of inflammation and the emergence of an immunosuppressive niche, coinciding with PanIN formation. CONCLUSIONS: Our findings define a conserved program of acinar plasticity across exocrine pancreas diseases. We further link unresolved ADM to immune remodeling during precursor lesion formation and observe the emergence of pancreatic cancer subtypes in early PanIN lesions.
2025-12-22 | GSE314765 | GEO
Project description:Both pancreatic intraepithelial neoplasia (PanIN), a frequent precursor of pancreatic cancer, and intraductal papillary mucinous neoplasm (IPMN), a less common precursor, undergo several phases of molecular conversions and finally develop into highly malignant solid tumors with negative effects on the quality of life. We approached this long-standing issue by examining the following PanIN/IPMN cell lines derived from mouse models of pancreatic cancer: Ptf1a–Cre; KrasG12D; p53f/+ and Ptf1a–Cre; KrasG12D; Brg1f/f PDAs. The mRNA from these cells was subjected to a cap analysis of gene expression (CAGE) to map the transcription starting sites and quantify the expression of promoters across the genome.
2019-11-13 | GSE139648 | GEO
Project description:We investigated transcriptional profiles of Ptf1a-Cre driven homozygous Tbx3-KO and wildtype pancreata 72h and 168h after onset of acute pancreatitis.
2023-02-24 | GSE216889 | GEO
Project description:The fundamental biology of pancreatic ductal adenocarcinoma has been greatly impacted by the characterization of genetically engineered mouse models that allow temporal and spatial activation of oncogenic KRAS (KRASG12D). One of the most commonly used models involves targeted insertion of a cre-recombinase into the Ptf1a gene. However, this approach disrupts the Ptf1a gene, resulting in haploinsufficiency that likely affects sensitivity to oncogenic KRAS (KRASG12D). This study aims to determine if Ptf1a haploinsufficiency affected the acinar cell response to KRASG12D before and after induction of pancreatic injury. Taken together, our results suggest Ptf1a haploinsufficiency in Ptf1acreERT mouse models promotes KRASG12D priming of genes for promotion of PDAC.
2024-08-20 | GSE252884 | GEO
Project description:Pancreatic ductal adenocarcinoma (PDAC) is an aggressive, painful disease with a 5-year survival rate of only 9%. Recent evidence indicates that distinct epigenomic landscapes underlie PDAC progression, identifying the H3K9me pathway as important to its pathobiology. Here, we delineate the role of Euchromatic Histone-lysine N-Methyltransferase 2 (EHMT2), the enzyme that generates H3K9me, as a downstream effector of oncogenic KRAS during PDAC initiation and pancreatitis-associated promotion. EHMT2 inactivation in pancreatic cells reduces H3K9me2 and antagonizes KrasG12D mediated acinar-to-ductal metaplasia (ADM) and PanIN formation in both the Pdx1-Cre and P48+/-Cre KrasG12D mouse models. Ex vivo acinar explants also show impaired EGFR-KRAS-MAPK pathway mediated ADM upon EHMT2 deletion. Notably, KrasG12D increases EHMT2 protein levels and EHMT2-EHMT1-WIZ complex formation. Transcriptome analysis reveals that EHMT2 inactivation upregulates a cell cycle inhibitory gene expression network that converges on the Cdkn1a/p21-Chek2 pathway. Congruently, pancreas tissue from KrasG12D animals with EHMT2 inactivation have increased P21 protein levels and enhanced senescence. Furthermore, loss of EHMT2 reduces inflammatory cell infiltration typically induced during KrasG12D-mediated initiation. The inhibitory effect on KrasG12D-induced growth is maintained in the pancreatitis-accelerated model, while simultaneously modifying immunoregulatory gene networks that also contribute to carcinogenesis. This study outlines the existence of a novel KRAS-EHMT2 pathway that is critical for mediating the growth-promoting and immunoregulatory effects of this oncogene in vivo, extending human observations to support a pathophysiological role for the H3K9me pathway in PDAC.
2021-07-01 | GSE169525 | GEO
Project description:Transgenic KrasG12D mice can recapitulate pancreas intra-epithelial neoplasia (PanIN). Caerulein is a cholecystokinin analogue and induces acute pancreatitis when injected intra-abdominally. Caerulein-induced acute pancreatitis will accelerate PanIN progression in KrasG12D mice. We compared mRNA profile changes between KrasG12D mice with acute caerulein-induced pancreatitis and wild-type mice without acute pancreatitis.
2016-05-14 | GSE77983 | GEO
Project description:The apical-basal polarity of pancreatic acinar cells is essential for maintaining tissue architecture. However, the mechanisms by which polarity proteins regulate acinar pancreas tissue homeostasis are poorly understood. Here, we evaluate the role of Par3 in acinar pancreas injury and homeostasis. While Par3 loss in the mouse pancreas disrupts tight junctions, Par3 loss is dispensable for pancreatogenesis. However, with aging, Par3 loss results in low-grade inflammation, acinar degeneration, and pancreatic lipomatosis. Par3 loss also exacerbates pancreatitis-induced acinar cell loss, resulting in pronounced pancreatic lipomatosis and failure to regenerate. Moreover, Par3 loss in mice harboring mutant Kras causes extensive pancreatic intraepithelial neoplastic (PanIN) lesions and large pancreatic cysts. We also show that Par3 loss restricts injury-induced primary ciliogenesis. Significantly, targeting BET proteins enhances primary ciliogenesis during pancreatitis-induced injury and, in mice with Par3 loss, limits pancreatitis-induced acinar loss and facilitates acinar cell regeneration. Combined, this study demonstrates how Par3 restrains pancreatitis- and Kras-induced changes in the pancreas and identifies a potential role for BET inhibitors to attenuate pancreas injury and facilitate pancreas tissue regeneration.
2024-08-05 | GSE243623 | GEO
Project description:BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDAC) is usually incurable. Contrary to genetic mechanisms involved in PDAC pathogenesis, epigenetic alterations are ill defined. Here we determine the contribution of epigenetically silenced genes to the development of PDAC. METHODS: We investigated methylated DNAs from PDACs, chronic pancreatitis and normal pancreatic tissues using Methyl-CpG immunoprecipitation followed by microarray hybridization. Promoter methylation of selected genes was confirmed with the Epityper assay. Expression levels were evaluated by quantitative RT-PCR. WNK2 was further investigated in tissue microarrays, methylation analysis of early pancreatic intraepithelial neoplasia (PanINs), mouse models for PDAC and pancreatitis, re-expression studies after demethylation, and cell growth assays using WNK2 overexpression. RESULTS: A total of 3.8% of 27.800 interrogated CpG islands were hypermethylated in PDAC versus normal and chronic pancreatitis tissues. Hypermethylation was confirmed in 12 out of 13 selected islands and was associated with gene silencing in 4 of them. The most prominently hypermethylated gene, WNK2, was further investigated. Demethylation assays confirmed the link between methylation and expression. WNK2 hypermethylation was higher in pancreatic tumor cells than in surrounding inflamed tissues and was observed in PanIN lesions as well as in a PDAC mouse model. WNK2 mRNA and protein expression were lower in PDAC and chronic pancreatitis compared to normal tissues both in patients and mouse models. Overexpression of WNK2 led to a reduced cell growth and WNK2 expression in tissues correlated negatively with the expression of pERK1/2, a downstream target of WNK2 responsible for cell proliferation. CONCLUSIONS: WNK2 is downregulated by promoter hypermethylation early in PDAC pathogenesis and may support tumor cell growth via the ERK-MAPK pathway. 3 types of pancreatic tissue samples: 5 normals, 2 chronic pancreatitis, 7 tumors (PDAC)
2012-11-01 | E-GEOD-37480 | biostudies-arrayexpress