The Somatic Landscape of Schwannoma
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE81145 | GEO | 2016/10/10
SECONDARY ACCESSION(S): PRJNA320735
REPOSITORIES: GEO
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Project description:Schwann cells are critical for the proper development and function of the peripheral nervous system, where they form a collaborative relationship with axons. Past studies highlighted that a pair of proteins called the prohibitins play major roles in Schwann cell biology. Prohibitins are ubiquitously expressed and versatile proteins. We have previously shown that while prohibitins play a crucial role in Schwann cell mitochondria for long-term myelin maintenance and axon health, they may also be present at the Schwann cell-axon interface during development. The current data set uses BioID to identify a pool of candidate PHB2 interactors in Schwann cells and explores how the PHB2 interactome changes depending on neuronal signals. We expressed a PHB2-turboID fusion construct in primary rat Schwann cells; turboID is a 35 kDa engineered biotin ligase that rapidly biotinylates proximal proteins. Thus, proteins interacting with PHB2-turboID within an approximately 10 nm radius are tagged with biotin. As a control, primary rat Schwann cells were transfected with an unfused turboID construct (Con-turboID). Schwann cells expressing Con-turboID or PHB2-turboID were plated alone or onto primary rat DRG neurons, in the presence or absence of biotin. After 2 hours, proteins were harvested from the cultures and biotinylated proteins were purified using streptavidin-affinity purification (AP). We then used liquid chromatography-mass spectrometry (LC-MS) to identify the PHB2-turboID interactors (the biotinylated proteins) in our purified pool. The PHB2 interactors identified here, especially those which increase or decrease interaction with PHB2-turboID in the presence of neurons, may play a role in prohibitin-associated Schwann cell-axon communication.
2024-09-02 | PXD054241 | Pride
Project description:Cerebral small vessel disease (CSVD) refers to a series of clinical, radiological, and pathological syndromes caused by various etiologies affecting small arteries, arterioles, venules, capillaries, and small veins in the brain. It can lead to cognitive impairment, stroke, gait abnormalities, and other neurological symptoms and signs. Globally, approximately 25% to 30% of strokes are caused by CSVD. The underlying mechanisms of CSVD are multifaceted, involving endothelial dysfunction, blood-brain barrier (BBB) inflammation, neuronal apoptosis, chronic cerebral hypoperfusion, and their complex interactions. Current treatments often fail to achieve satisfactory outcomes. Therefore, understanding the pathogenic mechanisms of CSVD is crucial for developing effective therapeutic strategies to mitigate its detrimental effects. The high-temperature requirement protease A-1 (HTRA1) mutations can cause hereditary CSVD. CSVD associated with HTRA1 mutations is referred to as HTRA1-associated CSVD. Homozygous HTRA1 mutations cause Cerebral Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CARASIL), a rare hereditary CSVD that is inherited in an autosomal recessive manner. Heterozygous HTRA1 mutations can lead to Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy type 2 (CADASIL 2), also known as heterozygous HTRA1 mutation carriers. This condition is characterized by clinical manifestations such as stroke, cognitive impairment, gait abnormalities, alopecia, and spondylosis. To date, 35 pathogenic mutations in the HTRA1 gene have been reported, primarily exhibiting autosomal dominant inheritance. Current research mainly focuses on case reports and the potential pathogenic mechanisms associated with different mutation sites. HTRA1 mutations can lead to downregulation of HTRA1 mRNA and protein expression, thereby reducing HTRA1 protease activity. However, the specific morphological and functional changes associated with CSVD, especially those in endothelial cells, remain unclear. This study aims to explore the mutation spectrum and clinical phenotypes of heterozygous HTRA1 mutation carriers. By comparing whole-blood RNA sequencing (RNA-seq) analysis between heterozygous HTRA1 mutation carriers and healthy controls, we identify differentially expressed genes. Based on the RNA-seq results, we further investigate the effects of abnormal HtrA1 expression on the biological functions of mouse brain microvascular endothelial cells and mouse cognitive behavior. This study elucidates the role of HTRA1 in CSVD, providing insights into the pathogenesis and new therapeutic targets for patients with heterozygous HTRA1 mutations.
2026-03-11 | GSE324041 | GEO
Project description:Cell state evolution underlies tumor development and response to therapy1, but mechanisms specifying cancer cell states and intratumor heterogeneity are incompletely understood. Schwannomas are the most common tumors of the peripheral nervous system and are treated with surgery and ionizing radiation2–5. Schwannomas can oscillate in size for many years after radiotherapy6,7, suggesting treatment may reprogram schwannoma cells or the tumor microenvironment. Here we show epigenetic reprogramming shapes the cellular landscape of schwannomas. We find schwannomas are comprised of 2 molecular groups distinguished by reactivation of neural crest development pathways or misactivation of nerve injury mechanisms that specify cancer cell states and the architecture of the tumor immune microenvironment. Schwannoma molecular groups can arise independently, but ionizing radiation is sufficient for epigenetic reprogramming of neural crest to immune-enriched schwannoma by remodeling chromatin accessibility, gene expression, and metabolism to drive schwannoma cell state evolution and immune cell infiltration. To define functional genomic mechanisms underlying epigenetic reprograming of schwannomas, we develop a technique for simultaneous interrogation of chromatin accessibility and gene expression coupled with genetic and therapeutic perturbations in single-nuclei. Our results elucidate a framework for understanding epigenetic drivers of cancer evolution and establish a paradigm of epigenetic reprograming of cancer in response to radiotherapy.
2023-04-18 | PXD014798 | Pride
Project description:Epigenome analysis of schwannoma tumor samples
2016-10-10 | GSE79009 | GEO
Project description: Not available
| S-EPMC10786948 | biostudies-literature
Project description:Loss of NF2 (merlin) has been suggested as a genetic cause of neurofibromatosis type 2 and malignant peripheral nerve sheath tumor (MPNST). Previously, we demonstrated that NF2 sustained TGF- receptor 2 (TR2) expression and reduction or loss of NF2 activated non-canonical TGF- signaling, which reduced RKIP expression via TR1 kinase activity. Here, we show that a selective RKIP inducer (novel chemical, Nf18001) inhibits tumor growth and promotes schwannoma cell differentiation into mature Schwann cells under NF2-deficient conditions. In addition, Nf18001 is not cytotoxic to cells expressing NF2 and is not disturb canonical TGF- signaling. Moreover, the novel chemical induces expression of SOX10, a marker of differentiated Schwann cells, and promotes nuclear export and degradation of SOX2, a stem cell factor. Treatment with Nf18001 inhibited tumor growth in an allograft model with mouse schwannoma cells. These results strongly suggest that selective RKIP inducers could be useful for the treatment of neurofibromatosis type 2 as well as NF2-deficient MPNST. To know the global effect of Nf18001, we performed the microarray with HEI-193.
2021-10-22 | GSE186107 | GEO
Project description:The HTRA1 gene encoding an evolutionary conserved protein quality control factor can be epigenetically silenced or inactivated by mutation under pathologic conditions such as cancer. Recent evidence suggests that loss of HTRA1 function causes multiple phenotypes including acceleration of cell growth, delayed onset of senescence, centrosome amplification and polyploidy suggesting an implication in the regulation of the cell cycle. To address this model, we performed a large-scale proteomics study to correlate the abundance of proteins and HTRA1 levels in various cell cycle phases using label-free quantification mass spectrometry. These data indicate that the levels of 4723 proteins fluctuated in a cell cycle-dependent, 2872 in a HTRA1-dependent and 1530 in a cell cycle- and HTRA1-dependent manner. The large number of proteins affected by the modulation of HTRA1 levels support its general role in protein homeostasis. Moreover, the detected changes in protein abundance in combination with pull down data implicate HTRA1 is in numerous cell cycle events such as DNA replication, chromosome segregation and cell cycle dependent apoptosis. These results highlight the wide implications of HTRA1 in cellular physiology
2019-02-15 | PXD007079 | Pride
Project description:Hearing loss (HL) is the most common sensory disorder in the world population. One common cause of hearing loss is the presence of vestibular schwannoma (VS) a benign tumor of the VIII cranial nerve, arising from Schwann cells (SCs) transformation. In the last decade, an increasing incidence of VSs may be ascribed to the exposure to electromagnetic field (EMF), which may be considered a pathogenic cause of VS development and HL. In this paper, we explore the possible molecular mechanisms underlying the biologic changes of human SCs and/or their oncogenic transformation following EMF exposure. We investigated, by NGS technology RNA-Seq transcriptomic analysis, the genomic profile and the differential display of HL-related genes following chronic EMF. We found that cell proliferation in parallel with intracellular signaling and metabolic pathways, mostly related to translation and mitochondrial activity were modified by chronic EMF exposure. Importantly, the expression of some HL-related genes, such as NEFL, TPRN, OTOGL, GJB2 and REST appeared regulated chronic EMF.
2021-07-28 | GSE174389 | GEO
Project description:ChIP-seq of H3K27acetylation in sham and injured nerve. Schwann cells play an important role in the response of peripheral nerve to injury. This study was designed to identify enhancers that are altered in sciatic nerve at 3 days post-injury to help identify pathways that mediate the gene expression reprogramming that occurs in Schwann cells after nerve injury. We employed ChIP-seq analysis of H3K27 acetylation as a mark of actively engaged enhancers, and compared enhancers in the distal stump of transected sciatic nerve compared to contralateral (sham) condition.
2014-12-15 | GSE63103 | GEO