Similar Datasets
Project description:The developmental integrity of bile duct epithelium and peribiliary glands (PBGs) plays a key role in maintaining bile flow and preventing liver diseases. We emplpoyed multilineage biliary organoids (MBOs) engineered from co-cultures of human liver epithelial cells, umbilical vein endothelial cells (HUVECs), and mesenchymal stem cells (MSCs) to model biliary development and pathogenesis of biliary atresia (BA). Self organization of these cells into MBOs recapitulated the dual compartmentalization of bile ducts with the epithelial layer and PBGs. Notably, BA patient-derived MBOs exhibited markers of epithelial-mesenchymal transition (EMT) and activated TGF-β/Activin-SMAD2/3 signaling pathways, suggesting a link to the delayed maturation of bile duct epithelium. Inhibition of TGF-β signaling suppressed EMT, promoted epithelial maturation, and improved organoid structure. In in vivo, TGF-β inhibitor treatment in a neonatal mouse model of BA reduced biliary injury and liver fibrosis. These data support the critical role of epithelial and mesenchymal cell interactions in bile duct development, give insight into molecular mechanisms of BA, and point to the therapeutic potential of targeting TGF-β signaling.
2025-06-10 | GSE264440 | GEO
Project description:The developmental integrity of bile duct epithelium and peribiliary glands (PBGs) plays a key role in maintaining bile flow and preventing liver diseases. We emplpoyed multilineage biliary organoids (MBOs) engineered from co-cultures of human liver epithelial cells, umbilical vein endothelial cells (HUVECs), and mesenchymal stem cells (MSCs) to model biliary development and pathogenesis of biliary atresia (BA). Self organization of these cells into MBOs recapitulated the dual compartmentalization of bile ducts with the epithelial layer and PBGs. Notably, BA patient-derived MBOs exhibited markers of epithelial-mesenchymal transition (EMT) and activated TGF-β/Activin-SMAD2/3 signaling pathways, suggesting a link to the delayed maturation of bile duct epithelium. Inhibition of TGF-β signaling suppressed EMT, promoted epithelial maturation, and improved organoid structure. In in vivo, TGF-β inhibitor treatment in a neonatal mouse model of BA reduced biliary injury and liver fibrosis. These data support the critical role of epithelial and mesenchymal cell interactions in bile duct development, give insight into molecular mechanisms of BA, and point to the therapeutic potential of targeting TGF-β signaling.
2025-06-10 | GSE264201 | GEO
Project description:Cellular crosstalk mediated by TGF-β drives epithelial-mesenchymal transition in patient-derived multilineage biliary organoids
| PRJNA1106050 | ENA
Project description:Cellular crosstalk mediated by TGF-β drives epithelial-mesenchymal transition in patient-derived multilineage biliary organoids [scRNA-seq]
| PRJNA1102405 | ENA
Project description:Cellular crosstalk mediated by TGF-β drives epithelial-mesenchymal transition in patient-derived multilineage biliary organoids [bulk RNA-seq]
| PRJNA1101451 | ENA
Project description:KRAS, an oncogene, is frequently activated by mutations in many cancers. Kras-driven adenocarcinoma development in the lung, pancreas, and biliary tract has been extensively studied using gene targeting in mice. By taking the organoid- and allograft-based genetic approach to these organs, essentially the same results as in vivo models were obtained in terms of tumor development. To verify the applicability of this approach to other organs, we investigated whether the combination of Kras activation and Pten inactivation, which gives rise to endometrial tumors in mice, could transform murine endometrial organoids in the subcutis of immunodeficient mice. We found that in KrasG12D-expressing endometrial organoids, Pten knockdown did not confer tumorigenicity, but Cdkn2a knockdown or Trp53 deletion led to the development of carcinosarcoma (CS), a rare, aggressive tumor comprising both carcinoma and sarcoma. Although they originated from epithelial cells, some CS cells expressed both epithelial and mesenchymal markers. Upon inoculation in immunodeficient mice, tumor-derived round organoids developed carcinoma or CS, whereas spindle-shaped organoids formed monophasic sarcoma only, suggesting an irreversible epithelial-mesenchymal transition during the transformation of endometrial cells and progression. As commonly observed in mutant Kras-driven tumors, the deletion of the wild-type Kras allele was identified in most induced tumors, whereas some epithelial cells in CS-derived organoids were unexpectedly negative for KrasG12D. Collectively, we showed that the oncogenic potential of KrasG12D and the histological features of derived tumors are context-dependent and varies according to the organ type and experimental settings. Our findings provide novel insights into the mechanisms underlying tissue-specific Kras-driven tumorigenesis.
| S-EPMC8233399 | biostudies-literature
Project description:Epithelial-mesenchymal transition (EMT) is a crucial event in wound healing, tissue repair and cancer progression in adult tissues. We have recently shown that transforming growth factor (TGF)-?-induced EMT involves isoform switching of fibroblast growth factor receptors by alternative splicing. We performed a microarray-based analysis at single exon level to elucidate changes in splicing variants generated during TGF-?-induced EMT, and found that TGF-? induces broad alteration of splicing patterns by downregulating epithelial splicing regulatory proteins (ESRPs). This was achieved by TGF-?-mediated upregulation of ?EF1 family proteins, ?EF1 and SIP1. ?EF1 and SIP1 each remarkably repressed ESRP2 transcription through binding to the ESRP2 promoter in NMuMG cells. Silencing of both ?EF1 and SIP1, but not either alone, abolished the TGF-?-induced ESRP repression. The expression profiles of ESRPs were inversely related to those of ?EF1 and SIP in human breast cancer cell lines and primary tumor specimens. Further, overexpression of ESRPs in TGF-?-treated cells resulted in restoration of the epithelial splicing profiles as well as attenuation of certain phenotypes of EMT. Therefore, ?EF1 family proteins repress the expression of ESRPs to regulate alternative splicing during TGF-?-induced EMT and the progression of breast cancers.
| S-EPMC3391666 | biostudies-literature
Project description:We found that in KrasG12D-expressing endometrial organoids, Pten knockdown did not confer tumorigenicity, but Cdkn2a knockdown or Trp53 deletion led to the development of carcinosarcoma (CS), a rare, aggressive tumor comprising both carcinoma and sarcoma.To better characterize the pathogenesis of CS from organoids, we conducted a transcriptome analysis.
2021-06-30 | GSE175512 | GEO
Project description:Glioblastoma (GBM) is the most common intrinsic and aggressive primary brain tumor in adults, with a median survival of approximately 15 months. GBM heterogeneity is considered responsible for the treatment resistance and unfavorable prognosis. Proneural-mesenchymal transition (PMT) represents GBM malignant progression and recurrence, which might be a breakthrough to understand GBM heterogeneity and overcome treatment resistance. PMT is a complicated process influenced by crosstalk between GBM and tumor microenvironment, depending on intricate ligand-receptor interactions. In this review, we summarize the autocrine and paracrine pathways in the GBM microenvironment and related ligand-receptor interactions inducing PMT. We also discuss the current therapies targeting the PMT-related autocrine and paracrine pathways. Together, this review offers a comprehensive understanding of the failure of GBM-targeted therapy and ideas for future tendencies of GBM treatment.
| S-EPMC10491977 | biostudies-literature
Project description:Background and purposeAirway remodelling is a critical feature of chronic lung diseases. Epithelial-mesenchymal transition (EMT) represents an important source of myofibroblasts, contributing to airway remodelling. Here, we investigated the sphingosine-1-phosphate (S1P) role in EMT and its involvement in asthma-related airway dysfunction.Experimental approachA549 cells were used to assess the S1P effect on EMT and its interaction with TGF-β signalling. To assess the S1P role in vivo and its impact on lung function, two experimental models of asthma were used by exposing BALB/c mice to subcutaneous administration of either S1P or ovalbumin (OVA).Key resultsFollowing incubation with TGF-β or S1P, A549 acquire a fibroblast-like morphology associated with an increase of mesenchymal markers and down-regulation of the epithelial. These effects are reversed by treatment with the TGF-β receptor antagonist LY2109761. Systemic administration of S1P to BALB/c mice induces asthma-like disease characterized by mucous cell metaplasia and increased levels of TGF-β, IL-33 and FGF-2 within the lung. The bronchi harvested from S1P-treated mice display bronchial hyperresponsiveness associated with overexpression of the mesenchymal and fibrosis markers and reduction of the epithelial.The S1P-induced switch from the epithelial toward the mesenchymal pattern correlates to a significant increase of lung resistance and fibroblast activation. TGF-β blockade, in S1P-treated mice, abrogates these effects. Finally, inhibition of sphingosine kinases by SK1-II in OVA-sensitized mice, abrogates EMT, pulmonary TGF-β up-regulation, fibroblasts recruitment and airway hyperresponsiveness.Conclusion and implicationsTargeting S1P/TGF-β axis may hold promise as a feasible therapeutic target to control airway dysfunction in asthma.
| S-EPMC9306821 | biostudies-literature