Brain-wide neuronal circuit connectome of human glioblastoma [bulk RNA-seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE274633 | GEO | 2024/12/20
REPOSITORIES: GEO
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Project description:This study explores the circuit integration of human glioblastoma organoids (GBOs) in vivo in the adult mouse brain. We performed single cell RNA sequencing (scRNA-seq) to understand the cell state diversity of malignant tumor cells in GBOs at baseline and after stimulation by 1 mM acetylcholine (ACh) for 1 hour. Sliced neocortical organoids (SNOs) were also sequenced to study gene expression properties of neural stem cells (NSCs).
2024-12-20 | GSE274460 | GEO
Project description:Brain-wide neuronal circuit connectome of human glioblastoma
| PRJNA1146457 | ENA
Project description:Brain-wide neuronal circuit connectome of human glioblastoma [bulk RNA-seq]
| PRJNA1147310 | ENA
Project description:Acetylcholine (ACh) has been considered a neurotransmitter residing in central, parasympathetic and neuromuscular synapses of mammals. Here, experiments using crypt-villus organoids that lack nerve and immune cells in culture led us to suggest that endogenous ACh is synthesized in the intestinal epithelium to evoke growth and differentiation of the organoids through activation of muscarinic ACh receptors (mAChRs). The extracts of the cultured organoids exhibit a noticeable capacity for ACh synthesis that is sensitive to a potent inhibitor of choline acetyltransferase (ChAT). Imaging mass spectrometry reveals distribution of endogenous ACh that is localized in intestinal epithelial layer in the cultured organoids as well as in mouse small intestinal epithelium in vivo, suggesting non-neural resources of ACh. Treatment of organoids with carbachol down-regulates growth of organoids and expression of marker gene for each epithelial cell. On the other hand, antagonists for mAChRs enhances growth and differentiation of organoids, indicating involvement of mAChRs in regulating proliferation and differentiation of Lgr5-positive stem cells. Collectively, our data provide evidence that endogenous ACh released from intestinal epithelium maintains homeostasis of intestinal epithelial cell growth and differentiation via mAChRs in mice. Gene expression patters of gut, crypt, y-organoid and o-organoid, respectively
2013-08-15 | E-GEOD-49864 | biostudies-arrayexpress
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:We have developed a nonheuristic genome topography scan (GTS) algorithm to characterize the patterns of genomic alterations in human glioblastoma (GBM), identifying frequent p18INK4C and p16INK4A codeletion. Functional reconstitution of p18INK4C in GBM cells null for both p16INK4A and p18INK4C resulted in impaired cell-cycle progression and tumorigenic potential. Conversely, RNAi-mediated depletion of p18INK4C in p16INK4A-deficient primary astrocytes or established GBM cells enhanced tumorigenicity in vitro and in vivo. Furthermore, acute suppression of p16INK4A in primary astrocytes induced a concomitant increase in p18INK4C. Together, these findings uncover a feedback regulatory circuit in the astrocytic lineage and demonstrate a bona fide tumor suppressor role for p18INK4C in human GBM wherein it functions cooperatively with other INK4 family members to constrain inappropriate proliferation. Keywords: SuperSeries DNA copy number and mRNA transcriptome of human glioblastoma tumors were profiled using Agilent and Affymetrix microarrays. This SuperSeries is composed of the following subset Series: GSE7602: Human GBM tumor vs Normal Human DNA GSE9171: Expression data from human GBM tumors and cell lines GSE9177: Human GBM tumor vs Normal Human DNA
2008-04-29 | E-GEOD-9200 | biostudies-arrayexpress
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:Acetylcholine (ACh) has been considered a neurotransmitter residing in central, parasympathetic and neuromuscular synapses of mammals. Here, experiments using crypt-villus organoids that lack nerve and immune cells in culture led us to suggest that endogenous ACh is synthesized in the intestinal epithelium to evoke growth and differentiation of the organoids through activation of muscarinic ACh receptors (mAChRs). The extracts of the cultured organoids exhibit a noticeable capacity for ACh synthesis that is sensitive to a potent inhibitor of choline acetyltransferase (ChAT). Imaging mass spectrometry reveals distribution of endogenous ACh that is localized in intestinal epithelial layer in the cultured organoids as well as in mouse small intestinal epithelium in vivo, suggesting non-neural resources of ACh. Treatment of organoids with carbachol down-regulates growth of organoids and expression of marker gene for each epithelial cell. On the other hand, antagonists for mAChRs enhances growth and differentiation of organoids, indicating involvement of mAChRs in regulating proliferation and differentiation of Lgr5-positive stem cells. Collectively, our data provide evidence that endogenous ACh released from intestinal epithelium maintains homeostasis of intestinal epithelial cell growth and differentiation via mAChRs in mice.
2013-08-15 | GSE49864 | GEO
Project description:Animals use spatial differences in environmental light levels for visual navigation; however, how light inputs are translated into coordinated motor outputs remains poorly understood. Here we reconstruct the neuronal connectome of a four-eye visual circuit in the larva of the annelid Platynereis using serial-section transmission electron microscopy. In this 71-neuron circuit, photoreceptors connect via three layers of interneurons to motorneurons, which innervate trunk muscles. By combining eye ablations with behavioral experiments, we show that the circuit compares light on either side of the body and stimulates body bending upon left-right light imbalance during visual phototaxis. We also identified an interneuron motif that enhances sensitivity to different light intensity contrasts. The Platynereis eye circuit has the hallmarks of a visual system, including spatial light detection and contrast modulation, illustrating how image-forming eyes may have evolved via intermediate stages contrasting only a light and a dark field during a simple visual task.
| S-EPMC4059887 | biostudies-literature
Project description:We have developed a nonheuristic genome topography scan (GTS) algorithm to characterize the patterns of genomic alterations in human glioblastoma (GBM), identifying frequent p18INK4C and p16INK4A codeletion. Functional reconstitution of p18INK4C in GBM cells null for both p16INK4A and p18INK4C resulted in impaired cell-cycle progression and tumorigenic potential. Conversely, RNAi-mediated depletion of p18INK4C in p16INK4A-deficient primary astrocytes or established GBM cells enhanced tumorigenicity in vitro and in vivo. Furthermore, acute suppression of p16INK4A in primary astrocytes induced a concomitant increase in p18INK4C. Together, these findings uncover a feedback regulatory circuit in the astrocytic lineage and demonstrate a bona fide tumor suppressor role for p18INK4C in human GBM wherein it functions cooperatively with other INK4 family members to constrain inappropriate proliferation. This SuperSeries is composed of the SubSeries listed below.
2008-04-29 | GSE9200 | GEO