Mechanosensitive ion channel regulates tissue stiffening to promote glioma aggression
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ABSTRACT:
PROVIDER: PRJNA450606 | ENA |
REPOSITORIES: ENA
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Project description:Tissue stiffening is a physical hallmark of solid tumor. In our study, we found that the mechanosensitive ion channel PIEZO1 can be tumor cells force sensor and transducer that regulate the altered tissue mechanics. We examined the transcriptional changes modulated by depletion of PIEZO1 in two human GBM cell lines. We found that with PIEZO1 KD, the components involved in ECM organization, focal adhesion formation, cytoskeleton, and mitosis, which contribute to tissue stiffness, are down-regulated.
2018-10-18 | GSE113261 | GEO
Project description:Myocardial damage caused for example by cardiac ischemia leads to ventricular volume overload resulting in increased stretch of the remaining myocardium. In adult mammals, these changes trigger an adaptive cardiomyocyte hypertrophic response which, if the damage is extensive, will ultimately lead to pathological hypertrophy and heart failure. Conversely, in response to extensive myocardial damage, cardiomyocytes in the adult zebrafish heart and neonatal mice proliferate and completely regenerate the damaged myocardium. We therefore hypothesized that in adult zebrafish, changes in mechanical loading due to myocardial damage may act as a trigger to induce cardiac regeneration. Based, on this notion we sought to identify mechanosensors which could be involved in detecting changes in mechanical loading and triggering regeneration. Here we show using a combination of knockout animals, RNAseq and in vitro assays that the mechanosensitive ion channel Trpc6a is required by cardiomyocytes for successful cardiac regeneration in adult zebrafish. Furthermore, using a cyclic cell stretch assay, we have determined that Trpc6a induces the expression of components of the AP1 transcription complex in response to mechanical stretch. Our data highlights how changes in mechanical forces due to myocardial damage can be detected by mechanosensors which in turn can trigger cardiac regeneration.
2023-12-20 | E-MTAB-13603 | biostudies-arrayexpress
Project description:Ion channels play critical roles in the physiology and function of the nervous system and contractile tissue; however, their role in non-contractile tissue and embryonic development has yet to be understood. Tracheobronchomalacia (TBM) and complete tracheal rings (CTR) are disorders affecting the muscle and cartilage of the trachea and bronchi, whose etiology remains poorly understood. We demonstrated that trachealis muscle organization and polarity are disrupted after epithelial ablation of Wls, a cargo receptor critical for the Wnt signaling pathway, in developing trachea. The phenotype resembles the anomalous trachealis muscle observed after deletion of ion channel encoding genes in developing mouse trachea. We sought to investigate whether and how the deletion ofWlsaffects ion channels during tracheal development. We hypothesize that Wnt signaling influences the expression of ion channels to promote trachealis muscle cell assembly and patterning. Deleting Wls in developing trachea causes differential regulation of genes mediating actin binding, cytoskeleton organization, and potassium ion channel activity. Wnt signaling regulated expression of Kcnj13, Kcnd3, Kcnj8, and Abcc9 as demonstrated by in vitro studies and in vivo analysis in Wnt5a and b-catenin deficient tracheas. Pharmacological inhibition of potassium ion channels and Wnt signaling impaired contractility of developing trachealis smooth muscle and formation of cartilaginous mesenchymal condensation. Thus, in mice, epithelial-induced Wnt/b-catenin signaling mediates trachealis muscle and cartilage development via modulation of ion channel expression, promoting trachealis muscle architecture, contractility, and cartilaginous extracellular matrix. In turn, ion channel activity may influence tracheal morphogenesis underlying TBM and CTR.
2023-11-06 | GSE241175 | GEO
Project description:Plants respond to mechanical stressors in a variety of ways, producing electrical and biochemical signals, altering gene expression profiles, and changing organellar organization and morphology. We used a combination of genetic and proteomic approaches to identify genes that modify signaling of MSL10, a mechanosensitive ion channel in Arabidopsis which promotes programmed cell death in response to the mechanical stress from osmotic cell swelling. Mass spectrometry was used to identify proteins that co-immunoprecipitate with MSL10-GFP or with MSL107xD-GFP, a phosphomimetic variant that cannot activate cell death signaling. Interestingly, proteomics identified many proteins that are found at ER-plasma membrane contact sites (EPCSs). Two of the most abundant proteins that co-precipitated with MSL10 are the EPCS proteins VAP27-1 and SYT1, both of which have been reported to relocalize into spherical membrane structures in response to mechanical stress, a phenomenon also observed with MSL10. SYT1 has previously been shown to promote resistance to mechanical stress. A suppressor screen of the gain-of-function msl10-3G allele yielded mutants with point mutations in synaptotagmin (SYT)5 and SYT7, proteins that form a functional complex with SYT1. Together, these results suggest that MSL10 interacts with SYT1, SYT5, and SYT7 at EPCSs and that its cell death signaling output is modulated by this interaction.
2022-10-26 | PXD018747 | Pride
Project description:Extracellular biophysical cues such as matrix stiffness are key stimuli tuning cell fate and affecting tumor progression in vivo. However, it remains unclear how spheroids in a 3D microenvironment perceive matrix mechanical stiffness stimuli and translate them into intracellular signals driving cancer. Mechanosensitive Piezo1 and TRPV4 ion channels, upregulated in many malignancies, are major transducers of such physical stimuli into biochemical responses. Most mechanotransduction studies probing the reception of changing stiffness cues by cells are, however, still limited to 2D culture systems or cell-extracellular matrix models which lack the major cell-cell interactions prevalent in 3D cancer tumors. Here, we engineered a 3D spheroid culture environment with varying mechanobiological properties to study the effect of static matrix stiffness stimuli on mechanosensitive and malignant phenotypes in oral squamous cell carcinoma spheroids. We find that spheroid growth is enhanced when cultured in stiff extracellular matrix. Using flow cytometry, we show that the expression of mechanoreceptor Piezo1 and stemness marker CD44 is upregulated in stiff matrix. We also report the upregulation of a selection of genes with associations to mechanoreception, ion channel transport, extracellular matrix organization, and tumorigenic phenotypes in stiff matrix spheroids. Together, our results indicate that cancer cells in 3D spheroids utilize mechanosensitive ion channels Piezo1 and TRPV4 to sense changes in static extracellular matrix stiffness and that stiffness drives pro-tumorigenic phenotypes in oral squamous cell carcinoma.
2024-03-28 | GSE262142 | GEO
Project description:Ion channels and transporters have increasingly recognized roles in cancer progression through the regulation of cell proliferation, migration, and death. Glioblastoma stem-like cells (GSCs) are a source of tumor formation and recurrence in glioblastoma multiforme, a highly aggressive brain cancer, suggesting that ion channel expression may be perturbed in this population. However, little is known about the expression and functional relevance of ion channels that may contribute to GSC malignancy. Using RNA sequencing, we assessed the enrichment of ion channels in GSC isolates and non-tumor neural cell types. We identified a unique set of GSC-enriched ion channels using differential expression analysis that stratify by molecular subtype and are associated with distinct gene mutation signatures. In support of potential clinical relevance, expression of selected GSC-enriched ion channels evaluated in human glioblastoma databases of The Cancer Genome Atlas and Ivy Glioblastoma Atlas Project correlated with patient survival times. Finally, genetic knockdown or pharmacological inhibition of individual or classes of GSC-enriched ion channels constrained growth of GSCs compared to normal neural stem cells. This first-in-kind global examination characterizes ion channels enriched in GSCs and explores their potential clinical relevance to glioblastoma molecular subtypes, gene mutations, survival outcomes, regional tumor expression, and experimental responses to loss-of-function. Together, the data support the potential biological and therapeutic impact of ion channels on GSC malignancy and provide strong rationale for further examination of their mechanistic and therapeutic importance.
2017-04-21 | GSE89623 | GEO
Project description:The purpose of this study was to utilize RNAseq to determine if there are changes in ion channel mRNA expression in the retina of C57BL/6 mice subjected to the Microbead Occlusion Model. Whole retina was isolated from 2 month old mice that received intracameral injections of either saline or 15-um-diameter microbeads. Total RNA was isolated from the retinas and subjected to RNA sequencing using Illumina HiSeq 2500. Fold change in mRNA expression was compared between saline- and microbead-injected samples. We then analyzed these data for changes in expression of potassium channels, such as tandem-pore domain K+ channels, inwardly rectifying K+ channels, and the Na+/K+-ATPase.
2018-10-01 | GSE116915 | GEO
Project description:Long-lasting activation of T cells requires up-regulation of many genes, for example of transcription factors, cytoskeletal proteins and cell surface proteins encluding ion channels. An increase of ion channel density at the cell surface reflects the needs to manage increased Ca2+ influx into the activated T cell. Using oligonucleotide-based arrays we have surveyed changes in ion channel mRNA expression that occur upon T cell activation.
2010-06-17 | GSE22387 | GEO
Project description:Membrane ion channels of the calcium homeostasis modulator (CALHM) family promote cell-cell crosstalk at synapses via ATP release, where ATP acts as a neurotransmitter. CALHM6, the only CALHM highly expressed in immune cells, has been linked to induction of natural killer (NK) cell anti-tumour activity. Its mechanism of action and broader functions in the immune system are, however, unclear. Here we generated Calhm6-/- mice and report that CALHM6 is important for regulating the early innate control of Listeria monocytogenes infection in vivo. We find that CALHM6 is upregulated in macrophages by pathogen-derived signals, and that it relocates from intracellular compartment to the macrophage-NK cell synapse, facilitating ATP release and controlling the kinetics of NK cell activation. Anti-inflammatory cytokines terminate CALHM6 expression. CALHM6 forms an ion channel when expressed in the plasma membrane of Xenopus oocytes, where channel opening is controlled by a conserved acidic residue, E119, but CALHM6 is localized to intracellular compartments in mammalian cells. Our results contribute to understanding of neurotransmitter-like signal exchange between immune cells that fine-tunes the timing of innate immune responses.
2023-02-01 | GSE223008 | GEO
Project description:RNAseq quantitative analysis of ion channel mRNA expression in microbead occlusion model
| PRJNA480596 | ENA