Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA256159 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy characterized by an immunosuppressive tumor microenvironment enriched with cancer associated fibroblasts (CAFs). This study provides a convergence approach to identify tumor cell and CAF interactions through the integration of single-cell data from human tumors with human organoid co-culture. Analysis of a comprehensive atlas of PDAC single-cell RNA sequencing (scRNA-seq) data associates CAF density with increased inflammation and epithelial-mesenchymal transition (EMT) in epithelial cells. Transfer learning to transcriptional data from patient-derived organoid and CAF co-cultures provides in silico validation of CAF induction of inflammatory and EMT epithelial cell states. Further experimental validation in co-cultures demonstrates integrin beta 1 (ITGB1) and vascular endothelial factor A (VEGF-A) interactions with Neuropilin-1 (NRP1) mediating CAF and epithelial crosstalk. This study introduces transfer learning from human single-cell data to organoid co-culture for experimental validation of discoveries of cell-cell crosstalk, and identifies fibroblast-mediated regulation of EMT and inflammation.
2024-10-14 | GSE246812 | GEO
Project description:Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy characterized by an immunosuppressive tumor microenvironment enriched with cancer associated fibroblasts (CAFs). This study provides a convergence approach to identify tumor cell and CAF interactions through the integration of single-cell data from human tumors with human organoid co-culture. Analysis of a comprehensive atlas of PDAC single-cell RNA sequencing (scRNA-seq) data associates CAF density with increased inflammation and epithelial-mesenchymal transition (EMT) in epithelial cells. Transfer learning to transcriptional data from patient-derived organoid and CAF co-cultures provides in silico validation of CAF induction of inflammatory and EMT epithelial cell states. Further experimental validation in co-cultures demonstrates integrin beta 1 (ITGB1) and vascular endothelial factor A (VEGF-A) interactions with Neuropilin-1 (NRP1) mediating CAF and epithelial crosstalk. This study introduces transfer learning from human single-cell data to organoid co-culture for experimental validation of discoveries of cell-cell crosstalk, and identifies fibroblast-mediated regulation of EMT and inflammation.
2024-10-14 | GSE245319 | GEO
Project description:Myeloid cells coordinate T cell immune evasion in cancer yet are pliable and possess anti-tumor potential. Here, by co-targeting activation molecules we leverage the myeloid compartment as a therapeutic vulnerability in cancer. Myeloid cells in solid tumors expressed activation receptors including the pattern recognition receptor CLEC7A and the TNF receptor superfamily member CD40. In mouse models of checkpoint inhibitor-resistant pancreatic cancer, co-activation of CLEC7A, via systemic β-glucan therapy, and CD40, with agonist antibody treatment, eradicated established tumors and induced immunological memory. Anti-tumor activity was dependent on a cDC1 – T cell axis but did not require classical T cell cytotoxicity or blockade of checkpoint molecules. Rather, targeting CD40 drove T cell-derived IFNγ signaling which converged with CLEC7A activation to program distinct macrophage subsets to facilitate tumor responses. Thus, productive cancer immune surveillance can be invoked by co-activation of complementary myeloid signaling pathways.
2023-11-10 | GSE232860 | GEO
Project description:Mediator, a co-regulator required for RNA pol II activity, interacts with tissue-specific transcription factors to regulate development and maintain homeostasis. We sought to understand whether Mediator subunit MED15 acts as a node that controls tissue-specific gene expression, using pancreatic insulin-producing β-cell maturation as a model. We found Med15 to be expressed during mouse pancreatic organogenesis and β-cell maturation; moreover, islets from human T2D donors feature reduced MED15 expression. Loss of Med15 in mouse β-cells caused defects in maturation without affecting β-cell mass or insulin expression. ChIP-seq and co-immunoprecipitation analyses determined that Med15 binds β-cell transcription factors Nkx6-1 and NeuroD1 to regulate key β-cell maturation genes. Human embryonic stem cell derived β-like cells, genetically engineered to express high levels of MED15, had increased maturation markers and improved insulin secretion. We provide the first evidence of the importance of Mediator in β-cell maturation and demonstrate an additional layer of control that tunes transcription factor function.
2024-09-10 | GSE137145 | GEO
Project description:Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer fatalities in Western societies, characterized by high metastatic potential and resistance to chemotherapy. Critical molecular mechanisms of these phenotypical features still remain unknown, thus hampering the development of effective prognostic and therapeutic measures in PDAC. Here we show that transcriptional co-factor Transducin beta-like (TBL) 1 was over-expressed in both human and murine PDAC. Inactivation of TBL1 in human and mouse pancreatic cancer cells reduced cellular proliferation and enhanced chemosensitivity, correlating with diminished glucose uptake, glycolytic flux, and PI3kinase signaling. TBL1 deficiency both prevented and reversed pancreatic tumor growth in mice, triggering transcriptional PI3kinase inhibition also in vivo. As TBL1 mRNA levels were also found to correlate with overall and disease-free survival in a cohort of human PDAC patients and to predict therapy responsiveness in these subjects, TBL1 expression may serve both as a novel prognostic marker and molecular target in the treatment of human PDAC. Capan-1 cells were transfected with control-siRNA (#1027292, Qiagen) or siRNA against human TBL1 (SI04329514, Qiagen) and RNA was isolated 24h later
2015-06-16 | E-GEOD-59761 | biostudies-arrayexpress
Project description:Transcription factors harbour defined intrinsically disordered regulatory regions, which raises the question of how they mediate binding to structured co-regulators and how this regulates activity. Here, we present a detailed molecular regulatory mechanism of Forkhead box O4 (FOXO4) by the structured transcriptional co-regulator β-catenin. We find that the largely disordered FOXO4 C-terminal region, which contains its transactivation domain binds β-catenin through two defined interaction sites, and this is regulated by combined PKB/AKT- and CK1-mediated phosphorylation. Binding of β-catenin competes with the auto-inhibitory interaction of the FOXO4 disordered region with its DNA-binding forkhead domain, and thereby enhances FOXO4 transcriptional activity. Furthermore, we show that binding of the β-catenin inhibitor protein ICAT is compatible with FOXO4 binding to β-catenin, suggesting that ICAT acts as a molecular switch between anti-proliferative FOXO and pro-proliferative Wnt/TCF/LEF signalling. Together these data illustrate how the interplay of intrinsically disordered regions, post-translational modifications and co-factor binding contribute to transcription factor function. Highlights • The interaction network between FOXO4 and β-catenin was deciphered • FOXO4 auto-inhibition interferes with DNA binding and is counter-acted by β-catenin • FOXO4 exists in multiple conformations regulated by phosphorylation and co-factors • ICAT switches between FOXO4 and TCF/LEF transcription factors
2022-04-15 | PXD026263 | Pride
Project description:Tetraspanin CD63 acts as a pro-metastatic factor via β-catenin stabilization
| PRJNA262812 | ENA
Project description:Transcriptional and posttranscriptional regulatory networks play a crucial role in the maintenance and adaptation of pancreatic beta-cell function. In this study we show that the levels of the prototypic neuroendocrine miRNA-7 are regulated in islets of obese, diabetic and aged mouse models. Using gain- and loss-of-function models we demonstrate that miR-7 regulates crucial members of the endocrine pancreatic transcriptional network controlling differentiation and insulin synthesis. Importantly, it also directly regulates key proteins in the insulin granule secretory machinery. These results reveal an interconnecting miR-7 genomic circuit that influences beta-cell differentiation, insulin synthesis and release and define a role for miR-7 as an endocrine checkpoint to stabilize beta-cell function during metabolic stress. These findings have implications for miR-7 inhibitors as potential therapies for type 2 diabetes and neurodegenerative diseases. Either miR-7a2 or miR-7b were over-expressed in MIN6 cells using an adenoviral vector. The miR-7a infection was performed in duplicates. In addition, a GFP over-expression in MIN6 using the same viral vector served as control. We also explored the consequence of miR-7a2 deletion in pancreatic beta-cells by generating a beta-cells specific miR-7a2 knock-out using the Lox/Cre system in a C57BL/6 background. We profiled gene expression in mutant and wild-type (control) islets.
2015-06-30 | E-GEOD-48195 | biostudies-arrayexpress
Project description:Checkpoint inhibitors (CPIs) targeting PD-1/PD-L1 and CTLA-4 have revolutionized cancer treatment but can trigger autoimmune complications including CPI-induced diabetes (CPI-DM), which occurs preferentially with PD-1 blockade. We found evidence of pancreatic inflammation in patients with CPI-DM with shrinkage of pancreases, increased pancreatic enzymes, and in a case from a patient who died with CPI-DM, peri-islet lymphocytic infiltration. In the NOD mouse model, anti-PD-L1 but not anti-CTLA-4 induces DM rapidly. RNA sequencing revealed that cytolytic IFNγ+ CD8+ T cells infiltrated islets with anti-PD-L1. Changes in β cells were predominantly driven by IFNγ and TNFα and included induction of a novel β cell population with transcriptional changes suggesting dedifferentiation. IFNγ increased checkpoint ligand expression and activated apoptosis pathways in human β cells in vitro. Treatment with anti-IFNγ and anti-TNFα prevented CPI-DM in anti-PD-L1 treated NOD mice. CPIs targeting the PD-1/PD-L1 pathway result in transcriptional changes in β cells and immune infiltrates that may lead to the development of diabetes. Inhibition of inflammatory cytokines can prevent CPI-DM, suggesting a strategy for clinical application to prevent this complication.
2022-10-27 | GSE209587 | GEO
Project description:Checkpoint inhibitors (CPIs) targeting PD-1/PD-L1 and CTLA-4 have revolutionized cancer treatment but can trigger autoimmune complications including CPI-induced diabetes (CPI-DM), which occurs preferentially with PD-1 blockade. We found evidence of pancreatic inflammation in patients with CPI-DM with shrinkage of pancreases, increased pancreatic enzymes, and in a case from a patient who died with CPI-DM, peri-islet lymphocytic infiltration. In the NOD mouse model, anti-PD-L1 but not anti-CTLA-4 induces DM rapidly. RNA sequencing revealed that cytolytic IFNγ+ CD8+ T cells infiltrated islets with anti-PD-L1. Changes in β cells were predominantly driven by IFNγ and TNFα and included induction of a novel β cell population with transcriptional changes suggesting dedifferentiation. IFNγ increased checkpoint ligand expression and activated apoptosis pathways in human β cells in vitro. Treatment with anti-IFNγ and anti-TNFα prevented CPI-DM in anti-PD-L1 treated NOD mice. CPIs targeting the PD-1/PD-L1 pathway result in transcriptional changes in β cells and immune infiltrates that may lead to the development of diabetes. Inhibition of inflammatory cytokines can prevent CPI-DM, suggesting a strategy for clinical application to prevent this complication.
2022-10-27 | GSE208644 | GEO