PIKfyve controls dendritic cell function and tumor immunity II
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE235599 | GEO | 2023/06/26
REPOSITORIES: GEO
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Project description:To understand the mechanism of Pikfyve loss in dendritic cells, we cultured conventional dendritic cells isolated from the bone marrow of Pikfyvef/f (“WT”) and mice with ItgaxTg/0 Pikfyvef/f (“KO”) mice and performed transcriptome profiling on RNA extracted from cells on Day 9 in culture. Taken together, these data demonstrate the PIKfyve mediates suppression of DC transcriptional maturation programs through the alternate/non-canonical NF-κB regulatory pathway.
2023-06-26 | GSE235596 | GEO
Project description:RNA sequencing analysis of human iPSC-derived motor neurons generated from one C9ORF72 ALS/FTD patient line, treated with DMSO or Apilimod. The goal of this study is to evaluate the effect of PIKFYVE inhibitor in rescuing ALS motor neuron degeneration.
2022-12-18 | GSE221015 | GEO
Project description:PIKfyve controls dendritic cell function and tumor immunity II
| PRJNA986531 | ENA
Project description:PIKfyve controls dendritic cell function and tumor immunity I
| PRJNA986528 | ENA
Project description:Transcriptomics analysis of human coronary artery smooth muscle cells cultured in osteogenic medium and PIKfyve inhibition. To study the underlying molecular mechanisms of PIKfyve-mediated vascular calcification, we analyzed the transcriptome of osteogenic medium (OM)-calcified human coronary artery smooth muscle cells that were treated with PIKfyve inhibitors (Apilimod, YM201636) or DMSO control on day 7.
2025-12-31 | GSE284683 | GEO
Project description:This study aims to elucidate the transcriptomic changes and metabolic reprogramming in gastroenteropancreatic neuroendocrine tumor (GEP-NET) cells following PIKfyve inhibition, using both genetic (CRISPR-mediated knockdown) and pharmacological (Apilimod treatment) approaches. The research focuses on the impact of PIKfyve inhibition on lipid metabolism, cholesterol homeostasis, and mTOR signaling in QGP-1, BON-1, and GOT-1 cell lines. By analyzing RNA sequencing data from these experimental conditions, we seek to identify differentially expressed genes and enriched pathways associated with PIKfyve inhibition. This investigation is part of a broader effort to develop novel combination therapies that could potentially overcome resistance to mTOR inhibitors, the current standard of care for advanced GEP-NETs. The study's findings may provide insights into the therapeutic potential of targeting PIKfyve-driven lipid metabolism in combination with mTOR inhibition, potentially offering new strategies to improve treatment efficacy and patient outcomes in GEP-NETs and other mTOR-driven cancers.
2026-01-26 | GSE293842 | GEO
Project description:The cellular cytotoxicity of APY0201, a PIKfyve inhibitor, against multiple myeloma was initially identified in an unbiased in vitro chemical library screen. Activity was confirmed in all 25 cell lines tested and 40% of 100 ex vivo patient derived primary samples, and positively correlated with samples harboring trisomies and inversely related to t(11;14). The broad anti- multiple myeloma activity of PIKfyve inhibitors was further demonstrated in confirmatory screens and showed the superior potency of APY0201 when compared to the PIKfyve inhibitors YM201636 and apilimod, with a mid-point EC50 at nanomolar concentrations respectively in 65%, 40%, and 5% of the tested cell lines. An up-regulation of genes in the lysosomal pathway and increased cellular vacuolization was observed in vitro in cell lines following APY0201 treatment however this cellular response did not correlate well with responsiveness. We confirm that PIKfyve inhibition is associated with activation of the transcription factor EB, a master regulator of lysosomal biogenesis and autophagy. Furthermore, we established an assay measuring autophagy as a predictive marker of APY0201 sensitivity. Overall, these findings suggest promising activity of PIKfyve inhibitors secondary to disruption of autophagy in multiple myeloma and a strategy to enrich for likely responders.
2019-09-19 | GSE134598 | GEO
Project description:This study aims to elucidate the transcriptomic changes and metabolic reprogramming in gastroenteropancreatic neuroendocrine tumor (GEP-NET) cells following PIKfyve inhibition, using both genetic (CRISPR-mediated knockdown) and pharmacological (Apilimod treatment) approaches. The research focuses on the impact of PIKfyve inhibition on lipid metabolism, cholesterol homeostasis, and mTOR signaling in QGP-1, BON-1, and GOT-1 cell lines. By analyzing RNA sequencing data from these experimental conditions, we seek to identify differentially expressed genes and enriched pathways associated with PIKfyve inhibition. This investigation is part of a broader effort to develop novel combination therapies that could potentially overcome resistance to mTOR inhibitors, the current standard of care for advanced GEP-NETs. The study's findings may provide insights into the therapeutic potential of targeting PIKfyve-driven lipid metabolism in combination with mTOR inhibition, potentially offering new strategies to improve treatment efficacy and patient outcomes in GEP-NETs and other mTOR-driven cancers.
2026-01-26 | GSE293843 | GEO
Project description:Background Vascular calcification contributes to cardiovascular disease. One important process is the phenotypic transition of vascular smooth muscle cells (SMCs) from a contractile to a mineralizing phenotype, releasing calcifying extracellular vesicles (EVs). The endolysosomal system is involved in EV biogenesis and regulates essential cell physiological functions. We hypothesize that alterations in endomembrane homeostasis affect SMC phenotypic identity and EV cargo, thereby regulating vascular calcification. Results In human calcified carotid plaques and calcifying SMCs, the abundance of FYVE-Type Zinc Finger Containing Phosphoinositide Kinase (PIKfyve), an essential lipid kinase, in the endomembrane maturation, is increased. Phosphatidylinositol 3-phosphate (PI3P) - the substrate of PIKfyve - was decreased in cellular membranes of calcifying SMCs (-40%) and recovered by Apilimod, a small molecule PIKfyve inhibitor. In vitro, Apilimod reduced the osteogenic features, like matrix mineralization (-77%), collagen secretion (-99%), and tissue non-specific alkaline phosphatase (TNAP) protein expression (-86%) in calcifying SMCs. Moreover, Apilimod-induced EVs exhibited fewer mineral-positive EVs and reduced aggregation potential (-80%), suggesting diminished EV calcification potential. A proteomic analysis of the EV cargo demonstrated that Apilimod reduces TNAP cargo, which was supported by western blot. In a murine atherosclerosis model, Apilimod reduced aortic calcification assessed by ex vivo osteosense imaging. Transcriptomics revealed phenotypic transitions of calcifying SMCs after PIKfyve inhibition. Apilimod promoted adipogenic markers (PPARG: +218%, FABP3: +2250%), fatty acid uptake (+86%), lipid droplets (OilRed, Raman spectroscopy), and increased the expression of macrophage-like SMC markers (CD68: +500%; LGALS3: +132%), suggesting an alternative SMC phenotype. Kinome and in silico analyses identified YAP1 deactivation as a potential mechanism. Re-activation of YAP1 partially antagonized Apilimod-dependent effects in calcifying SMCs. Conclusion PIKfyve inhibition inhibits the osteogenic transition of SMCs while promoting a phenotypic adaptation towards adipogenic/pro-inflammatory SMCs, which is partially mediated by YAP1. The phenotypic identity of calcifying SMCs is sensitive to alterations of the endomembrane homeostasis.
2026-01-17 | PXD060400 | Pride
Project description:Dendritic cell (DC) vaccines have been proposed as cancer immunotherapies due to their role as crucial antigen-presenting cells that regulate T cell functions. Despite considerable efforts to optimize ex vivo priming of DCs, DC vaccines have rarely been successful, suggesting the presence of unknown inhibitory factors. Here, we examined DC differentiation dynamics and discovered that ALDH1a2-produced retinoic acid (RA) acts as a bottleneck factor, initiating negative feedback to inhibit DC maturation. Removing this inhibition through either genetic knockout or pharmacological blockade using KyA33, an ALDH1a2 inhibitor we developed, significantly enhances DC maturation, phagocytosis, antigen presentation, and T cell activation, in part by downregulating glucose metabolism. KyA33 demonstrates favorable drug-like properties, including low toxicity, high membrane permeability, and low cell efflux rate. Its non-covalent binding to ALDH1A2 was also validated through X-ray crystallography. Importantly, application of KyA33 generates more robust DCs vaccines, promoting anti-tumor immunity through enhancing antigen-specific T cell responses. Our investigation highlights the intricate interplay between retinoid signaling, dendritic cell maturation, and immune metabolism, offering promising avenues for enhancing cancer immunotherapies.
2025-11-03 | MTBLS10389 | MetaboLights