Targeting myoferlin in ER/Golgi vesicle trafficking reprograms cancer-associated fibroblasts in pancreatic cancer.
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ABSTRACT:
PROVIDER: PRJNA1312077 | ENA |
REPOSITORIES: ENA
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Project description:Pancreatic cancer cells exploit vesicle trafficking proteins such as myoferlin to fuel tumor aggressiveness, yet the presence and function of myoferlin-dependent vesicles in cancer-associated fibroblasts (CAFs) remain unknown. By combining PDAC whole-tumor and single-cell transcriptomic analyses with immunohistochemistry and 2D/3D in vitro models, we link stromal myoferlin to tumor aggressiveness. We identify CAF-specific functions of myoferlin, as MYOF-depleted CAFs present reduced activity and impaired extracellular matrix (ECM) production. Analysis of intracellular vesicles identifies a TGFß-receptor 1 (TGFBR1) trafficking blockade at the ER/Golgi interface upon myoferlin depletion, leading to altered TGFBR1 activation, impaired signal transduction, loss of ECM production and reduced CAF contractility. The genetic depletion of myoferlin in the murine tumor stroma and the pharmacological targeting of myoferlin alike reduced tumor desmoplasia in orthotopic KPC mice. Overall, we propose TGFBR1 trafficking as innovative target to reprogram CAFs, control desmoplasia and tackle these aggressive features in pancreatic cancer.
2025-08-28 | GSE306772 | GEO
Project description:Androgen receptor (AR) plays an essential role in normal prostate development and prostate cancer (PCa) progression. To understand the role of AR at the single-cell level, we performed single-cell transcriptome analysis on PCa cells stimulated with androgen and antiandrogen to reconstruct the dynamic and direct AR transcriptional network. Our work reveals that androgen stimulates the ER and Golgi stress response , promoting secreting protein trafficking, and inhibiting cell apoptosis. Moreover, we identify an ER-to-Golgi protein vesicle-mediated transport gene signature essential for maximal androgen-mediated ER-Golgi trafficking, cell proliferation, and association with PCa prognosis and progression. Notably, we show that AR collaborates with CREB3L2, XXX, to coordinately promote ER-Golgi trafficking of Golgi enzyme Mannosidase II and PCa cell survival. Finally, we show the inhibition of the ER-Golgi transport process with Brefeldin A leads to tumor regression. Our study collectively reveals the heterogeneity of PCa cell transcriptional response to androgen stimulation, demonstrates a functional role for increased ER-Golgi trafficking process, and provides a mechanism for how the process is augmented in PCa as well as the potential of targeting may provide novel treatment strategies.
2021-10-10 | GSE165562 | GEO
Project description: Not available
| S-EPMC12623807 | biostudies-literature
Project description:Compelling evidence indicates that defects in nucleocytoplasmic transport contribute to the pathogenesis of amyotrophic lateral sclerosis (ALS). In particular, hexanucleotide (G4C2) repeat expansions in C9orf72, the most common cause of genetic ALS, have a widespread impact on the transport machinery that regulates the nucleocytoplasmic distribution of proteins and RNAs, thereby affecting their functions. We have previously reported that the expression of G4C2 hexanucleotide repeats in cultured human and mouse cells caused a marked accumulation of poly(A) mRNAs in cell nuclei, suggesting that mRNA trafficking is impaired by expanded C9orf72-ALS repeats. To further characterize the process, in this work we set out to systematically identify the specific mRNAs that are altered in their nucleocytoplasmic distribution in the presence of C9orf72-ALS repeats. Results from RNAseq profiling of nuclear and cytoplasmic RNA fractions obtained from cells expressing G4C231 repeats show a significant accumulation of mRNAs in the nuclei of G4C231 cells, further suggesting that nuclear retention of mRNAs is a major effect of C9orf72 expanded repeats expression. Interestingly, pathway analysis shows that mRNAs involved in ER-to-Golgi trafficking are particularly enriched among the identified mRNAs. Most importantly, functional studies in cultured cells and Drosophila indicate that the membrane trafficking route regulated by ARFGAP1, a GTPase-activating protein that associates with Golgi, is specifically affected by expanded C9orf72 repeats, as well as by C9orf72-related dipeptide repeat proteins (C9-DPRs), pointing to ER-to-Golgi vesicle-mediated transport as a target of C9orf72 toxicity.
2023-08-21 | GSE235448 | GEO
Project description:Golgi biogenesis is a crucial cellular process, yet its study has been hindered by the lack of easy methods to induce massive production of new Golgi units. In this study, we optimized an enzyme inactivation approach to stimulate the formation of fully functional Golgi stacks. Massive Golgi biogenesis was achieved through DAB-mediated inactivation of preexisting Golgi structures in cells stably expressing the chimeric Golgi enzyme Mannosidase II fused with horse radish peroxidase (HRP). Within 10 to 18 hours post-Golgi inactivation, substantial number of cells regenerated new Golgi stacks capable of transporting various cargo proteins to their appropriate destinations. This functional and structural recovery of the Golgi in ManII-HRP cells offers an efficient system to study Golgi biogenesis and associated cellular responses. We further explored transcriptomic changes in ManII-HRP cells, discovering that the extensive biogenesis of Golgi membranes induces the transcriptional activation of numerous Golgi-associated genes. These genes encode proteins involved in diverse functions such as glycosylation, membrane tethering, and ion/sugar transport. The timing of this gene transactivation correlates with the restoration of Golgi cisternae architecture and trafficking capabilities, suggesting that this transcriptional response plays an integral role in the biogenesis of new Golgi units.
2026-05-13 | GSE288395 | GEO
Project description:Intracellular trafficking is essential for proper cell signaling. In the pancreas, secretory cells rely on trafficking to regulate blood glucose and digestion. Pancreatic disorders reflect defects in function or development, evoking considerable interest in understanding the molecular genetics governing pancreatic organogenesis. Here, we show the transcription factor NFIA regulates trafficking in both the embryonic and adult pancreas, affecting both developmental cell fate decisions and adult physiology. NFIA deletion from pancreatic progenitors led to the development of more acinar cells and ducts and fewer endocrine cells, whereas ectopic NFIA promoted endocrine formation. We found that NFIA’s effects on trafficking influence endocrine/exocrine cell fate decisions through regulation of Notch. Adult NFIA-deficient mice develop diabetic phenotypes due to impaired insulin granule trafficking and defects in acinar zymogen secretion. This study shows how a single transcription factor, NFIA, thus exerts profound effects on both embryonic cell fate and adult physiology by regulating vesicle trafficking.
2017-09-14 | GSE86909 | GEO
Project description:The anterograde secretory pathway shapes the extracellular environment and the ability of cells to communicate, through the release of cytokines, growth factors, enzymes and extracellular matrix components, and through the regulation of the composition of the plasma membrane (PM). The underlying molecular machinery operates in a concerted and highly regulated manner and is frequently altered in cancer. The Golgi RabGAP protein TBC1D22B is overexpressed in breast cancer and predicts prognosis. Herein, deconvolution of the proximity-labeling and physical interactomes of TBC1D22B, reveals its role in the regulation of anterograde trafficking with liaisons with networks of proteins involved in cell adhesion, and in carbohydrate and lipid metabolism. The function of TBC1D22B in the anterograde pathway was formally demonstrated using the Retention Using Selective Hooks system which synchronizes transport of cargoes from the ER to the Golgi and the PM. TBC1D22B inhibits ER to Golgi transport in a GAP-dependent manner. RAB1B, a key RAB in the early secretory pathway, was found to be a substrate of the TBC1D22B GAP activity, and its silencing phenocopied TBC1D22B overexpression. Thus, TBC1D22B regulates ER to Golgi trafficking through its ability to work as a GAP for RAB1B.
2025-08-21 | PXD060457 | Pride
Project description:Single-Cell Analysis Reveals Androgen Receptor Regulates ER-to-Golgi Trafficking with CREB3L2 To Drive Prostate Cancer Progression
| PRJNA694969 | ENA
Project description: Not available
| S-SCDT-10_1038-S44318-025-00570-6 | biostudies-other
Project description:Impaired proinsulin processing is observed in both type 1 and type 2 diabetes. We have previously shown that reductions in endoplasmic reticulum (ER) calcium (Ca2+) in the pancreatic β cell arising from impaired activity of the Sarcoendoplasmic Reticulum Ca2+ ATPase (SERCA) pump are associated with increased proinsulin secretion. However, the mechanisms responsible for reduced proinsulin processing in the context of SERCA2 deficiency remain incompletely understood. To test this, we developed mice with β cell specific SERCA2 deletion (βS2KO mice) and S2KO INS1 cells. βS2KO mice exhibited age-dependent glucose intolerance and reduced glucose-stimulated insulin secretion without evidence of impaired insulin sensitivity. ER Ca2+ levels in islets from βS2KO mice were significantly reduced, while serum proinsulin/insulin (PI/I) ratios and whole pancreas PI/I content were elevated. Immunoblot analysis of βS2KO islets and S2KO INS-1 cells revealed reduced active forms of the proinsulin processing enzymes, PC1/3, PC2 and CPE. Restoration of SERCA2b via adenoviral transduction in S2KO INS1 cells was sufficient to restore PC1/3 and PC2 maturation and enzyme activity. Brefeldin A treatment in INS1 cells recapitulated the impairments in PC1/3 and PC2 maturation observed in S2KO cells, suggesting a disturbance in protein trafficking between the ER and Golgi. Consistent with this, trafficking assays were performed using a vesicular stomatitis virus G (VSVG) protein construct and revealed a significantly slower rate of VSVG movement from the ER to the Golgi in S2KO INS1 cells. Moreover, pancreas sections from βS2KO mice showed increased co-localization of proinsulin and ProPC2 in the early compartments of the secretory pathway. Taken together, these data suggest that loss of SERCA2 activity and ER Ca2+ loss in the pancreatic β cell leads to impaired proinsulin processing via reduced maturation and trafficking of proinsulin processing enzymes.
2023-10-11 | GSE207498 | GEO