Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1101971 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28794143_1.fastq.gz | Fastqsanger.gz | |||
| SRR28794144_1.fastq.gz | Fastqsanger.gz | |||
| SRR28794196_1.fastq.gz | Fastqsanger.gz | |||
| SRR28794197_1.fastq.gz | Fastqsanger.gz |
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Project description:T cells exclusion precludes checkpoint inhibition efficacy in pancreatic ductal adenocarcinoma (PDA) and is mediated by the interaction between T cell CXCR4, and its ligand CXCL12, which is complexed to keratin-19 (KRT19) on the surface of PDA cells. KRT19 secretion is essential to this process but is unusual because KRT19 lacks an endoplasmic reticulum (ER)-directing signal peptide (SP). By using ER-restricted TurboID sys-tems and a split-GFP assay, we demonstrate that KRT19 enters the ER via its “head” domain. In vivo, tumors formed with ER-TurboID cells contain biotinylated KRT19. Additionally, KRT19 is shown to interact with the sig-nal recognition particle and its secretion is sensitive to canonical protein secretion inhibitors. Although keratin-8 (KRT8) co-localizes with KRT19 on the surface of PDA cells, KRT8 does not enter the ER. However, both keratins are externalized via secretory autophagy. Thus, despite lacking a classical SP, PDA cells secrete KRT19 to protect against immune attack.
2025-06-16 | PXD051583 | Pride
Project description:Our studies indicate that cancer cells of carcinomas are coated with CXCL12 chemokine in covalent conjugation with keratin-19 (KRT19). Murine pancreatic ductal adenocarcinomas (PDA) formed with Krt19-edited cancer cells lack the CXCL12-coating and are infiltrated with T cells, compared to tumors formed with control sgScramble PDA cells. To probe the immunological role of this CXCL12-coating thoroughly, bulk RNA sequencing of subcutaneous (s/c) murine sgScramble PDA tumors and Krt19-edited PDA tumors were conducted.
2022-01-07 | GSE193027 | GEO
Project description:To investigate Keratin 19 (KRT19) expression dynamics in pancreatic development, we established a human pluripotent stem cell (PSC)-based KRT19-mCherry reporter system in various genetic backgrounds to monitor KRT19 expression from ist endogenous gene locus. A genuine differentiation protocol to generate mature pancreatic duct-like organoids (PDLO) was applied. While KRT19/mCherry expression became evident at early endoderm stage, mCherry signal was present in nearly all cells at pancreatic endoderm (PE) and pancreatic progenitor (PP) stage. Interestingly, despite homogenous KRT19 expression, the mCherry positivity dropped to 50% after ductal maturation, indicating a permanent switch from biallelic to monoallelic expression. DNA methylation profiling separated the distinct differentiation intermediates with site specific DNA methylation patterns occuring at the KRT19 locus during ductal maturation. Accordingly, the monoallelic switch was partially reverted upon treatment with a DNA-methyltransferase inhibitor.
2023-06-08 | GSE234345 | GEO
Project description:The autoreactive T cells that destroy beta cells in type 1 diabetes are largely targeting insulin signal peptide fragments. HLA knockout beta-cells have been proposed to create hypo-immune cells, but this strategy poses significant tumorigenic risks. As an alternative, we hypothesized that insulin signal peptide modification would give rise to beta-cells evading autoimmune recognition while maintaining insulin functionality. Here, we developed human beta-cell lines lacking endogenous insulin that we complemented with insulin carrying signal peptides from different hormones including chromogranin-A. We evaluated insulin synthesis, processing, secretion, activity, and immune evasion. Chromogranin-A signal peptide substitution directed insulin expression, maturation and secretion, maintaining physiological proinsulin/insulin ratios. Secreted insulin remained functional. Crucially, beta-cells expressing insulin with chromogranin-A signal peptide evaded recognition and killing by autoreactive T cells without inducing ER stress or compromising cellular identity. This approach may offer a targeted alternative to systemic immunosuppression to be used in stem-cell-derived therapies by engineering endogenous insulin locus.
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Project description:Our studies indicate that cancer cells of carcinomas are coated with CXCL12 chemokine in covalent conjugation with keratin-19 (KRT19). Murine pancreatic ductal adenocarcinomas (PDA) formed with Krt19-edited cancer cells lack the CXCL12-coating and are infiltrated with T cells, compared to tumors formed with control sgScramble PDA cells. To probe the immunological role of this CXCL12-coating thoroughly, bulk RNA sequencing of subcutaneous (s/c) murine sgScramble PDA tumors and Krt19-edited PDA tumors were conducted. As comparison, an immunogenic tumor model was also assessed. To do so, s/c sgScramble PDA tumors and PDA tumors formed with sgScramble cells exppressing doxcycline-inducible ovalbumin (icOVA) were harvested and processed for bulk RNA sequencing.
2022-01-04 | GSE192853 | GEO
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
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Project description:Background & Aims: Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest cancers with poor prognosis and bad therapy outcome. Therefore, mouse models are frequently used to study PDAC and pancreatic preneoplastic lesions. This study aims to evaluate a proposed progression model from acinar cells via acinar-to-ductal metaplasia (ADM) to mucinous tubular complexes (MTC) at transcriptomic level and to investigate the molecular changes behind acinar-cell derived preneoplastic lesions in a mouse model of PDAC. Methods: Spatial transcriptomics was combined with pathological characterization of preneoplastic lesions in p48Cre/+-LSL-KrasG12D/+ mice (n=5) using the 10x Visium® platform. Integration with the Mouse Cell Atlas (MCA) 2.0 single-cell dataset was performed. Bioinformatic analysis was conducted using different Python toolkits and by calculating a pseudotime along the progression axis. Findings were validated at the protein level using immunohistochemistry (IHC). Results: Transcriptional data aligned well with pathological annotations and single-cell data confirmed a decrease in acinar cells and an increase in ductal cells during ADM. Pseudotime analysis supported the progression from acinar cells via ADM to MTC, with marker gene expression patterns along this axis. Upregulation of Keratin 19 and Tetraspanin 8, and downregulation of Amylase 1 and Claudin 10, were observed. Claudin 18 was upregulated specifically in MTC, while Mesothelin and Cathepsin L peaked during ADM. Validation by IHC confirmed the expression of Keratin 19, Amylase 1, Claudin 18 and Mesothelin on protein level. Conclusions: This study confirms the development of MTC from ADM and identifies novel biomarkers along the preneoplastic progression axis in a mouse model of PDAC, advancing our understanding of early pancreatic cancer development.
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Project description:Mutations in HNF1A cause Maturity Onset Diabetes of the Young type 3, the second most frequent form of diabetes caused by single gene mutation. We generated human pancreatic stem cell-derived endocrine cells with mutations in HNF1A and show that HNF1A deficiency impairs scβ-cell fate, insulin granule maturation and the secretion of insulin in a glucose responsive manner. Single-cell RNA sequencing reveals that HNF1A orchestrates a network of genes involved in glucose metabolism, zinc transport, calcium ion binding and hormone exocytosis. Furthermore, in both patients and stem cell-derived β-cells, HNF1A deficiency altered the stoichiometry of secreted c-peptide to insulin. Sulfonylurea, used in the treatment of these patients, restored both insulin secretion and stoichiometry. Significantly, uncoupling of c-peptide and insulin secretion as described here questions the common practice in using c-peptide as a proxy to evaluate β-cell function. We also demonstrate that correction of the HNF1A locus restores function, providing a path to cell therapy.
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Project description:Mutations in HNF1A cause Maturity Onset Diabetes of the Young type 3, the second most frequent form of diabetes caused by single gene mutation. We generated human pancreatic stem cell-derived endocrine cells with mutations in HNF1A and show that HNF1A deficiency impairs scβ-cell fate, insulin granule maturation and the secretion of insulin in a glucose responsive manner. Single-cell RNA sequencing reveals that HNF1A orchestrates a network of genes involved in glucose metabolism, zinc transport, calcium ion binding and hormone exocytosis. Furthermore, in both patients and stem cell-derived β-cells, HNF1A deficiency altered the stoichiometry of secreted c-peptide to insulin. Sulfonylurea, used in the treatment of these patients, restored both insulin secretion and stoichiometry. Significantly, uncoupling of c-peptide and insulin secretion as described here questions the common practice in using c-peptide as a proxy to evaluate β-cell function. We also demonstrate that correction of the HNF1A locus restores function, providing a path to cell therapy.
2019-04-12 | GSE129653 | GEO