Glioma-neuronal circuit remodeling induces regional immunosuppression [RNA-Seq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1225606 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR32394954_1.fastq.gz | Fastqsanger.gz | |||
| SRR32394954_2.fastq.gz | Fastqsanger.gz | |||
| SRR32394956_1.fastq.gz | Fastqsanger.gz | |||
| SRR32394956_2.fastq.gz | Fastqsanger.gz |
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Project description:Glioma-neuronal circuit remodeling induces regional immunosuppression [visium]
| PRJNA1225607 | ENA
Project description:Neuronal activity-driven mechanisms impact glioblastoma cell proliferation and invasion (1–7), and glioblastoma remodels neuronal circuits (8,9). Distinct intratumoral regions maintain functional connectivity via a subpopulation of malignant cells that mediate tumor-intrinsic neuronal connectivity and synaptogenesis through their transcriptional programs (8). However, the effects of tumor-intrinsic neuronal activity on other cells, such as immune cells, remain unknown. Here we show that regions within glioblastomas displaying elevated connectivity are characterized by regional immunosuppression. This is accompanied by different cell compositions and inflammatory status of tumor-associated macrophages (TAMs) in the tumor microenvironment. In preclinical models, genetic knockout of Thrombospondin-1 (TSP1/Thbs1), a synaptogenic factor critical for glioma-induced neuronal circuit remodeling, in glioblastoma cells suppressed synaptogenesis and glutamatergic neuronal hyperexcitability. Moreover, this restored antigen-presentation and pro-inflammatory responses, promoted the infiltration of pro-inflammatory TAMs and CD8+ T-cells, and mitigated the immunosuppressive effect of TAMs on T-cell proliferation. Furthermore, pharmacological inhibition of glutamatergic excitatory neuronal signaling redirected TAMs toward a less immunosuppressive phenotype, resulting in prolonged mouse survival. Lastly, pharmacological inhibition of glutamatergic signaling showed potential to enhance the efficacy of immune cell-based therapy. Altogether, our results demonstrate previously unrecognized immunosuppression mechanisms resulting from glioma-neuronal circuit remodeling and suggest that targeting glioma-neuron-immune crosstalk could provide new avenues for immunotherapy.
2025-03-18 | GSE289934 | GEO
Project description:Neuronal activity-driven mechanisms impact glioblastoma cell proliferation and invasion (1–7), and glioblastoma remodels neuronal circuits (8,9). Distinct intratumoral regions maintain functional connectivity via a subpopulation of malignant cells that mediate tumor-intrinsic neuronal connectivity and synaptogenesis through their transcriptional programs (8). However, the effects of tumor-intrinsic neuronal activity on other cells, such as immune cells, remain unknown. Here we show that regions within glioblastomas displaying elevated connectivity are characterized by regional immunosuppression. This is accompanied by different cell compositions and inflammatory status of tumor-associated macrophages (TAMs) in the tumor microenvironment. In preclinical models, genetic knockout of Thrombospondin-1 (TSP1/Thbs1), a synaptogenic factor critical for glioma-induced neuronal circuit remodeling, in glioblastoma cells suppressed synaptogenesis and glutamatergic neuronal hyperexcitability. Moreover, this restored antigen-presentation and pro-inflammatory responses, promoted the infiltration of pro-inflammatory TAMs and CD8+ T-cells, and mitigated the immunosuppressive effect of TAMs on T-cell proliferation. Furthermore, pharmacological inhibition of glutamatergic excitatory neuronal signaling redirected TAMs toward a less immunosuppressive phenotype, resulting in prolonged mouse survival. Lastly, pharmacological inhibition of glutamatergic signaling showed potential to enhance the efficacy of immune cell-based therapy. Altogether, our results demonstrate previously unrecognized immunosuppression mechanisms resulting from glioma-neuronal circuit remodeling and suggest that targeting glioma-neuron-immune crosstalk could provide new avenues for immunotherapy.
2025-03-18 | GSE289935 | GEO
Project description:Astrocytes, the most abundant cells in the central nervous system, promote synapse formation and help refine neural connectivity. Although they are allocated to spatially distinct regional domains during development, it is unknown whether region-restricted astrocytes are functionally heterogeneous. Here we show that postnatal spinal cord astrocytes express several region-specific genes, and that ventral astrocyte-encoded Semaphorin3a (Sema3a) is required for proper motor neuron and sensory neuron circuit organization. Loss of astrocyte-encoded Sema3a led to dysregulated α−motor neuron axon initial segment orientation, markedly abnormal synaptic inputs, and selective death of α−but not of adjacent γ−motor neurons. Additionally, a subset of TrkA+ sensory afferents projected to ectopic ventral positions. These findings demonstrate that stable maintenance of a positional cue by developing astrocytes influences multiple aspects of sensorimotor circuit formation. More generally, they suggest that regional astrocyte heterogeneity may help to coordinate postnatal neural circuit refinement. 12 total samples consisting of three biological replicates each of flow sorted postnatal day 7 dorsal spinal cord astrocytes, ventral spinal cord astrocytes, dorsal SC non astrocytes, and ventral SC non astrocytes
2014-05-02 | E-GEOD-55054 | biostudies-arrayexpress
Project description:We sought to characterize methylome remodeling during regional metastasis. We profiled the DNA methylome (n=44) and transcriptome (n=36) of matched primary breast tumors and regional metastases.
2014-12-01 | GSE57968 | GEO
Project description:Astrocytes, the most abundant cells in the central nervous system, promote synapse formation and help refine neural connectivity. Although they are allocated to spatially distinct regional domains during development, it is unknown whether region-restricted astrocytes are functionally heterogeneous. Here we show that postnatal spinal cord astrocytes express several region-specific genes, and that ventral astrocyte-encoded Semaphorin3a (Sema3a) is required for proper motor neuron and sensory neuron circuit organization. Loss of astrocyte-encoded Sema3a led to dysregulated α−motor neuron axon initial segment orientation, markedly abnormal synaptic inputs, and selective death of α−but not of adjacent γ−motor neurons. Additionally, a subset of TrkA+ sensory afferents projected to ectopic ventral positions. These findings demonstrate that stable maintenance of a positional cue by developing astrocytes influences multiple aspects of sensorimotor circuit formation. More generally, they suggest that regional astrocyte heterogeneity may help to coordinate postnatal neural circuit refinement.
2014-05-02 | GSE55054 | GEO
Project description:Genome-wide DNA methylation profiling of of 44 matched primary breast tumors and metastases. We sought to characterize methylome remodeling during regional metastasis. We profiled the DNA methylome (n=44) and transcriptome (n=36) of matched primary breast tumors and regional metastases.
2014-12-01 | GSE58999 | GEO
Project description:Secreted molecules from active neurons promote glioma growth
2017-08-29 | GSE62563 | GEO
Project description:Postnatal remodeling of neuronal connectivity shapes mature nervous systems.1,2,3 The pruning of exuberant connections involves cell-autonomous and non-cell-autonomous mechanisms, such as neuronal activity. Indeed, experience-dependent competition sculpts various excitatory neuronal circuits.4,5,6,7,8,9 Moreover, activity has been shown to regulate growth cone motility and the stability of neurites and synaptic connections.10,11,12,13,14 However, whether inhibitory activity influences the remodeling of neuronal connectivity or how activity influences remodeling in systems in which competition is not clearly apparent is not fully understood. Here, we use the Drosophila mushroom body (MB) as a model to examine the role of neuronal activity in the developmental axon pruning of γ-Kenyon cells. The MB is a neuronal structure in insects, implicated in associative learning and memory,15,16 which receives mostly olfactory input from the antennal lobe.17,18 The MB circuit includes intrinsic neurons, called Kenyon cells (KCs), which receive inhibitory input from the GABAergic anterior paired lateral (APL) neuron among other inputs. The γ-KCs undergo stereotypic, steroid-hormone-dependent remodeling19,20 that involves the pruning of larval neurites followed by regrowth to form adult connections.21 We demonstrate that silencing neuronal activity is required for γ-KC pruning. Furthermore, we show that this is mechanistically achieved by cell-autonomous expression of the inward rectifying potassium channel 1 (irk1) combined with inhibition by APL neuron activity likely via GABA-B-R1 signaling. These results support the Hebbian-like rule "use it or lose it," where inhibition can destabilize connectivity and promote pruning while excitability stabilizes existing connections.
| S-EPMC10017263 | biostudies-literature
Project description:Gene expression profiling of distinct members of a neuronal circuit has the potential to identify candidate molecules and mechanisms that underlie the formation, organization and function of the circuit. To this end, we report here the application of a novel method to characterize RNAs from small numbers of specific Drosophila brain neurons, which belong to the circadian circuit. We identified three different sets of mRNAs enriched in different subclasses of clock neurons: one is enriched in all clock neurons, a second is enriched in PDF-positive clock neurons and a third is enriched in PDF-negative clock neurons. Moreover, we characterized 2 novel genes, Fer2 and dnocturnin, one from each subgroup, which highlight subgroup-specific features and play important roles in circadian rhythms. The methodology is a powerful tool not only to dissect the cellular and molecular basis of circadian rhythms but also to molecularly characterize other Drosophila neuronal circuits. Experiment Overall Design: Circadican related neuronal celltypes (Tim, Pdf) or general neurons (Elav) were labeled by GFP or YFP using specific Gal4 drivers. Expression of those celltypes were profiled after manual sorting of those GFP or YFP positive cells. 3 biological replicates were collected (except adult small pdf cells).
2009-11-10 | E-GEOD-17803 | biostudies-arrayexpress