Endocrine-exocrine signaling in obesity-driven pancreatic ductal adenocarcinoma
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PROVIDER: PRJNA544495 | ENA |
REPOSITORIES: ENA
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Project description:Endocrine-exocrine signaling in obesity-driven pancreatic ductal adenocarcinoma
| PRJNA564842 | ENA
Project description:Obesity is a major modifiable risk factor for pancreatic ductal adenocarcinoma (PDAC), yet how and when obesity contributes to PDAC progression is not well understood. Leveraging an autochthonous mouse model, we demonstrate a causal and reversible role for obesity in early PDAC progression, showing that obesity markedly enhances tumorigenesis, while genetic or dietary induction of weight loss intercepts cancer development. Bulk and single cell molecular analyses of human and murine samples define microenvironmental consequences of obesity that promote tumor development rather than new driver gene mutations. We observe increased inflammation and fibrosis and also provide evidence for significant pancreatic islet cell adaptation in obesity-associated tumors. Specifically, we identify aberrant beta islet cell expression of the peptide hormone cholecystokinin (CCK) in tumors as an adaptive response to obesity. Furthermore, islet CCK expression promotes oncogenic Kras-driven pancreatic ductal tumorigenesis. Our studies argue that PDAC progression is driven by local obesity-associated changes in the tumor microenvironment – rather than systemic effects – and implicate endocrine-exocrine signaling beyond insulin in PDAC development. Furthermore, our demonstration that these obesity-associated adaptations are reversible supports the use of anti-obesity strategies to intercept PDAC early during progression
2020-05-14 | GSE131714 | GEO
Project description:Obesity is a major modifiable risk factor for pancreatic ductal adenocarcinoma (PDAC), yet how and when obesity contributes to PDAC progression is not well understood. Leveraging an autochthonous mouse model, we demonstrate a causal and reversible role for obesity in early PDAC progression, showing that obesity markedly enhances tumorigenesis, while genetic or dietary induction of weight loss intercepts cancer development. Bulk and single cell molecular analyses of human and murine samples define microenvironmental consequences of obesity that promote tumor development rather than new driver gene mutations. We observe increased inflammation and fibrosis and also provide evidence for significant pancreatic islet cell adaptation in obesity-associated tumors. Specifically, we identify aberrant beta islet cell expression of the peptide hormone cholecystokinin (CCK) in tumors as an adaptive response to obesity. Furthermore, islet CCK expression promotes oncogenic Kras-driven pancreatic ductal tumorigenesis. Our studies argue that PDAC progression is driven by local obesity-associated changes in the tumor microenvironment – rather than systemic effects – and implicate endocrine-exocrine signaling beyond insulin in PDAC development. Furthermore, our demonstration that these obesity-associated adaptations are reversible supports the use of anti-obesity strategies to intercept PDAC early during progression.
2020-08-12 | GSE137236 | GEO
Project description:Pancreatic ducts form an intricate network of tubules that secrete bicarbonate and drive acinar secretions into the duodenum. This network is formed by centroacinar cells, terminal, intercalated, intracalated ducts, and the main pancreatic duct. Ductal heterogeneity at the single-cell level has been poorly characterized. Here, we used scRNA-seq to comprehensively characterize mouse ductal heterogeneity at single-cell resolution of the entire ductal epithelium from centroacinar cells to the main duct. Moreover, we used organoid cultures, injury models and pancreatic tumor samples to interrogate the role of novel ductal populations in pancreas regeneration and exocrine pathogenesis. In our study, we have identified the coexistence of 15 ductal populations within the healthy pancreas and characterized their organoid formation capacity and endocrine differentiation potential. Cluster isolation and subsequent culturing let us identify ductal cell populations with high organoid formation capacity and endocrine and exocrine differentiation potential in vitro, including Wnt-responsive-population, ciliated-population and FLRT3+ cells. Moreover, we have characterized the location of these novel ductal populations in healthy pancreas, chronic pancreatitis and tumor samples, hightlihgting a putative role of WNT-responsive, IFN-responsive and EMT-populations in pancreatic exocrine pathogenesis as their expression inceases in chronic pancreatitis and PanIN lesions. In light of our discovery of previously unidentified ductal populations, we unmask the potential roles of specific ductal populations in pancreas regeneration and exocrine pathogenesis.
2024-03-24 | GSE262292 | GEO
Project description:This project is reporting on microdissection proteomics of human operable, non-neoadjuvant treated pancreatic ductal adenocarcinomas (PDAC) with deep coverage of histologically neoplastic and adjacent healthier exocrine glands as well as stromal regions surrounding both. Through proteomic analysis, the parenchymal sample types differed significantly, with the malignant regions characterized by a broad downregulation of digestive enzymes. Instead, the stromal areas were alike, dominated by extracellular matrix proteins and lower expression of most metabolic pathways compared to the exocrine areas. Cholesterol synthesizing enzymes were more abundant in the tumor than stroma, as confirmed by an independent PDAC dataset and immunohistochemistry of PDAC microarrays. However, this was not accompanied by intratumor lipid deposition. Pathways most prognostic for survival were unexpectedly enriched in the histologically healthier exocrine glands, with a specific prognostic marker. Systematic analysis of pancreatic cancer transcriptomes from The Cancer Genome Atlas revealed that increased transcriptional complexity confers poor prognosis in PDAC.
2022-09-05 | PXD026371 | Pride
Project description:The Ppy-gene encodes the pancreatic polypeptide (PP) secreted by PP- or - cells, an endocrine cell type located in the islet periphery. For a detailed characterization of PP cells, we aimed to establish PP cell lines. To this end, we generated Ppy-Cre;Rosa26-CAG-LSL-Large T mice, in which the SV40 large T antigen (TAg) is expressed in Ppy-expressing cells upon Cre-loxP-mediated recombination. Ppy-Cre;Rosa26-CAG-LSL-Large T mice, surprisingly, developed pancreatic ductal adenocarcinoma (PDAC) rapidly by 3 to 4 weeks of age, while mice with insulin2-Cre-mediated activation of TAg developed insulinomas. This suggests that PDACs could arise from the islet/endocrine cells, which is rather unexpected as PDACs are generally believed to originate from the pancreatic acinar or ductal cells. RNA-seq analysis of transformed Ppy-lineage cells in 7-day old islets showed downregulation of endocrine genes, upregulation of exocrine, ductal genes, and upregulation of PDAC-related genes and pathways, respectively. These results suggest that expression of an oncogene in Ppy-lineage cells leads to a fate switch in these endocrine precursors that causes them to adopt a PDAC cell fate. Our findings revealed that Ppy-lineage cells may be one of the origins of PDAC and provide novel insights into the heterogeneity in pathogenesis of pancreatic cancer and its personalized therapy.
2024-06-01 | GSE245435 | GEO
Project description:Diabetes poses a tremendous threat to human health. Exocrine pancreatic dysfunction is related to diabetes, but the exact mechanism is not fully understood. In this study, the high-fat and high-sucrose dietary interventions were performed on diabetes susceptible transgenic pigs (PIGinH11) and wild pigs. And the molecular mechanism of pancreatic endocrine and exocrine damage was analyzed by histopathology and single nucleus RNA sequencing.
2023-04-22 | GSE226141 | GEO
Project description:Pancreatic ductal adenocarcinoma
| PRJNA432344 | ENA
Project description:Aims: establishment of reference samples to investigate gene expression selective for endocrine or ductal-exocrine cells within the adult human pancreas. To this end, human islet endocrine cells, FACS-enriched in insulin+ cells, (n=3) and human exocrine ductal cells (n=2) are compared on Affymetrix HG133A platform with duplicate hybridizations of a panel of other primary human tissues.
2011-07-21 | GSE30803 | GEO