Remote neuronal activity drives glioma progression via Sema4F
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE231800 | GEO | 2023/06/30
REPOSITORIES: GEO
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Project description:The tumor microenvironment (TME) plays an essential role in malignancy and neurons have emerged as a key component of the TME that promotes tumorigenesis across a host of cancers. Recent studies on glioblastoma (GBM) highlight bi-directional signaling between tumors and neurons that propagates a vicious cycle of proliferation, synaptic integration, and brain hyperactivity; however, the identity of neuronal subtypes and tumor subpopulations driving this phenomenon are incompletely understood. Here we show that callosal projection neurons located in the hemisphere contralateral to primary GBM tumors promote progression and widespread infiltration. Using this platform to examine GBM infiltration, we identified an activity dependent infiltrating population present at the leading edge of mouse and human tumors that is enriched for axon guidance genes. High-throughput, in vivo screening of these genes identified Sema4F as a key regulator of tumorigenesis and activity-dependent infiltration. Furthermore, Sema4F promotes the activity-dependent infiltrating population and propagates bi-directional signaling with neurons by remodeling tumor adjacent synapses towards brain network hyperactivity. Collectively, our studies demonstrate that subsets of neurons in locations remote to primary GBM promote malignant progression, while revealing new mechanisms of tumor infiltration that are regulated by neuronal activity.
| S-EPMC10055154 | biostudies-literature
Project description:Remote neuronal activity drives glioma progression via Sema4F
| PRJNA967706 | ENA
Project description:Mammalian tissues have a limited regenerative capacity. Previous studies showed that dedifferentiation contributes to tissue regeneration in non-mammalian vertebrate species such as zebrafish and newt. However, dedifferentiation is rarely observed in mammalian tissues even in the neonatal stage and therefore artificial induction of dedifferentiation might enhance regeneration in mammalian tissues. Here we demonstrate that short-term expression of Yamanaka 4 factors (4F) induces dedifferentiation and proliferation in the liver by using lineage-traceable, hepatocyte-specific 4F inducible mouse model. Global transcriptome analysis shows that 4F expression transiently reduces the expression of hepatic-lineage markers and induces the expression of a large set of proliferative markers and epigenetic modifiers along with global epigenetic changes as assessed by DNA-accessibility analysis. More importantly, lineage-tracing experiments showed that 4F-expressing hepatocytes acquire liver stem/progenitor cell markers, suggesting that 4F induces partial reprogramming. Moreover, 4F enhances MyoD-mediated transdifferentiation in the liver, suggesting that 4F endows hepatocytes with plasticity. Lastly, 4F expression attenuated liver injury associated with more proliferative capacity and better survival rate, indicating that 4F enhances liver regeneration. Taken together, these results demonstrate that liver-specific 4F expression induces dedifferentiation and promotes liver regeneration.
2022-04-27 | GSE144600 | GEO
Project description:Neurons have recently emerged as essential cellular constituents of the tumour microenvironment, and their activity has been shown to increase the growth of a diverse number of solid tumours1. Although the role of neurons in tumour progression has previously been demonstrated2, the importance of neuronal activity to tumour initiation is less clear-particularly in the setting of cancer predisposition syndromes. Fifteen per cent of individuals with the neurofibromatosis 1 (NF1) cancer predisposition syndrome (in which tumours arise in close association with nerves) develop low-grade neoplasms of the optic pathway (known as optic pathway gliomas (OPGs)) during early childhood3,4, raising the possibility that postnatal light-induced activity of the optic nerve drives tumour initiation. Here we use an authenticated mouse model of OPG driven by mutations in the neurofibromatosis 1 tumour suppressor gene (Nf1)5 to demonstrate that stimulation of optic nerve activity increases optic glioma growth, and that decreasing visual experience via light deprivation prevents tumour formation and maintenance. We show that the initiation of Nf1-driven OPGs (Nf1-OPGs) depends on visual experience during a developmental period in which Nf1-mutant mice are susceptible to tumorigenesis. Germline Nf1 mutation in retinal neurons results in aberrantly increased shedding of neuroligin 3 (NLGN3) within the optic nerve in response to retinal neuronal activity. Moreover, genetic Nlgn3 loss or pharmacological inhibition of NLGN3 shedding blocks the formation and progression of Nf1-OPGs. Collectively, our studies establish an obligate role for neuronal activity in the development of some types of brain tumours, elucidate a therapeutic strategy to reduce OPG incidence or mitigate tumour progression, and underscore the role of Nf1mutation-mediated dysregulation of neuronal signalling pathways in mouse models of the NF1 cancer predisposition syndrome.
| S-EPMC8346229 | biostudies-literature
Project description:The study investigates the role of NF1 mutation and neuronal activity on the initiation of optic pathway glioma, a type of low-grade glioma. the RNAseq dataset investigates mRNA expression profile of human pilocytic astrocytomas (WHO grade I)
2021-03-30 | GSE163071 | GEO
Project description:The apolipoprotein A-I (apoA-I) mimetic peptide 4F displays prominent anti-inflammatory properties, including the ability to reduce vascular macrophage content. Macrophages are a heterogenous group of cells, represented by two principal phenotypes, the classically activated M1 macrophage and an alternatively activated M2 phenotype. We recently reported that 4F favors the differentiation of human monocytes to an anti-inflammatory phenotype similar to that displayed by M2 macrophages. In the current study, microarray analysis of gene expression in monocyte-derived macrophages (MDMs) was carried out to identify inflammatory pathways modulated by 4F treatment. ApoA-I treatment of MDMs served as a control. Transcriptional profiling revealed that 4F and apoA-I modulated expression of 113 and 135 genes that regulate inflammatory responses, respectively. Cluster heat maps revealed that 4F and apoA-I induced similar changes in expression for 69 common genes. Modulation of other gene products, including STAT1 and PPARG, were unique for 4F treatment. Besides modulating inflammatory responses, 4F was found to alter gene expression in cell-to-cell signaling, cell growth/proliferation, lipid metabolism and cardiovascular system development. These data suggest that the protective effects of 4F in a number of disease states may be due to underlying changes in monocyte/macrophage gene expression. 16 samples analyzed (four 4F+LPS, four 4F, four Controls+LPS, four Controls).
2012-09-30 | E-GEOD-36933 | biostudies-arrayexpress
Project description:NF1 mutation drives neuronal activity-dependent optic glioma initiation
| PRJNA684596 | ENA
Project description:Core regularity transcription factors (CR TFs) define cell identity and lineage through an exquisitely precise and logical order during embryogenesis and development. These CR TFs regulated one another in three-dimensional space via distal enhancers that serve as logic gates embedded in their TF recognition sequences. Aberrant chromatin organization resulting in miswired circuitry of enhancer logic is a newly recognized feature in many cancers. Here, we report that PAX3-FOXO1 expression is driven by a translocated FOXO1 distal super enhancer (SE). ChIP-seq in tumors bearing rare PAX translocations implicate enhancer miswiring is a pervasive feature across all FP-RMS tumors. Therefore, our data reveal a mechanism of a translocated hijacked enhancer which disrupts the normal CR TF logic during skeletal muscle development (PAX3 to MYOD to MYOG), replacing it with an infinite loop logic that makes rhabdomyosarcoma cells unable to exit the undifferentiated proliferating stage.
2019-12-25 | GSE136799 | GEO
Project description:Background: The mitochondrial protein, translocator protein (TSPO), is a widely used biomarker of neuroinflammation, but its non-selective cellular expression pattern implies roles beyond inflammatory processes. The present study investigated whether neuronal activity modifies TSPO expression in the adult central nervous system. Methods: Single-cell RNA sequencing was performed to generate a cellular landscape of basal TSPO gene expression in the hippocampus of adult (12 weeks old) C57BL6/N mice, whereas confocal laser scanning microscopy was used to verify TSPO protein in neuronal and non-neuronal cell populations. TSPO RNA and protein were quantified after stimulating neuronal activity with distinct stimuli, including designer receptors exclusively activated by designer drugs (DREADDs), exposure to a novel environment and acute treatment with the psychostimulant drug, amphetamine. Results: Single-cell RNA sequencing demonstrated a non-selective and multi-cellular gene expression pattern of TSPO at basal conditions in the adult mouse hippocampus. Confocal laser scanning microscopy confirmed that TSPO protein is expressed in neuronal and non-neuronal (astrocytes, microglia, vascular endothelial cells) cells of cortical (medial prefrontal cortex) and subcortical (hippocampus) brain regions. Stimulating neuronal activity through chemogenetic (DREADDs), physiological (novel environment exposure) or psychopharmacological (amphetamine treatment) approaches led to consistent increases in TSPO gene and protein levels in neurons but not in microglia or astrocytes. Conclusions: Neuronal activity has the potential to modify TSPO expression in the adult central nervous system. These findings challenge the general assumption that altered TSPO levels unequivocally mirrors ongoing neuroinflammation and emphasize the need to consider non-inflammatory interpretations in some physiological or pathological contexts.
2022-05-01 | GSE150508 | GEO
Project description:The apolipoprotein A-I (apoA-I) mimetic peptide 4F displays prominent anti-inflammatory properties, including the ability to reduce vascular macrophage content. Macrophages are a heterogenous group of cells, represented by two principal phenotypes, the classically activated M1 macrophage and an alternatively activated M2 phenotype. We recently reported that 4F favors the differentiation of human monocytes to an anti-inflammatory phenotype similar to that displayed by M2 macrophages. In the current study, microarray analysis of gene expression in monocyte-derived macrophages (MDMs) was carried out to identify inflammatory pathways modulated by 4F treatment. ApoA-I treatment of MDMs served as a control. Transcriptional profiling revealed that 4F and apoA-I modulated expression of 113 and 135 genes that regulate inflammatory responses, respectively. Cluster heat maps revealed that 4F and apoA-I induced similar changes in expression for 69 common genes. Modulation of other gene products, including STAT1 and PPARG, were unique for 4F treatment. Besides modulating inflammatory responses, 4F was found to alter gene expression in cell-to-cell signaling, cell growth/proliferation, lipid metabolism and cardiovascular system development. These data suggest that the protective effects of 4F in a number of disease states may be due to underlying changes in monocyte/macrophage gene expression.
2012-09-30 | GSE36933 | GEO