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1.
Cell ; 180(3): 407-409, 2020 02 06.
Artículo en Inglés | MEDLINE | ID: mdl-32032515

RESUMEN

Diffuse gliomas inevitably progress, but our understanding of the molecular events associated with recurrence is limited. Recent work from the Glioma Longitudinal Analysis (GLASS) consortium (Barthel et al., 2019) reports temporal DNA sequencing on a large cohort of primary and recurrent glioma pairs, establishing the evolutionary molecular characteristics of adult diffuse gliomas.


Asunto(s)
Neoplasias Encefálicas , Glioma , Adulto , Estudios de Cohortes , Humanos , Recurrencia Local de Neoplasia , Análisis de Secuencia de ADN
2.
Nature ; 573(7775): 532-538, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31534219

RESUMEN

A network of communicating tumour cells that is connected by tumour microtubes mediates the progression of incurable gliomas. Moreover, neuronal activity can foster malignant behaviour of glioma cells by non-synaptic paracrine and autocrine mechanisms. Here we report a direct communication channel between neurons and glioma cells in different disease models and human tumours: functional bona fide chemical synapses between presynaptic neurons and postsynaptic glioma cells. These neurogliomal synapses show a typical synaptic ultrastructure, are located on tumour microtubes, and produce postsynaptic currents that are mediated by glutamate receptors of the AMPA subtype. Neuronal activity including epileptic conditions generates synchronised calcium transients in tumour-microtube-connected glioma networks. Glioma-cell-specific genetic perturbation of AMPA receptors reduces calcium-related invasiveness of tumour-microtube-positive tumour cells and glioma growth. Invasion and growth are also reduced by anaesthesia and the AMPA receptor antagonist perampanel, respectively. These findings reveal a biologically relevant direct synaptic communication between neurons and glioma cells with potential clinical implications.


Asunto(s)
Neoplasias Encefálicas/fisiopatología , Progresión de la Enfermedad , Glioma/fisiopatología , Sinapsis/patología , Animales , Neoplasias Encefálicas/ultraestructura , Modelos Animales de Enfermedad , Glioma/ultraestructura , Humanos , Ratones , Microscopía Electrónica de Transmisión , Neuronas/fisiología , Receptores AMPA/genética , Receptores AMPA/metabolismo
3.
Int J Cancer ; 151(9): 1431-1446, 2022 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-35603902

RESUMEN

Glial-lineage malignancies (gliomas) recurrently mutate and/or delete the master regulators of apoptosis p53 and/or p16/CDKN2A, undermining apoptosis-intending (cytotoxic) treatments. By contrast to disrupted p53/p16, glioma cells are live-wired with the master transcription factor circuits that specify and drive glial lineage fates: these transcription factors activate early-glial and replication programs as expected, but fail in their other usual function of forcing onward glial lineage-maturation-late-glial genes have constitutively "closed" chromatin requiring chromatin-remodeling for activation-glioma-genesis disrupts several epigenetic components needed to perform this work, and simultaneously amplifies repressing epigenetic machinery instead. Pharmacologic inhibition of repressing epigenetic enzymes thus allows activation of late-glial genes and terminates glioma self-replication (self-replication = replication without lineage-maturation), independent of p53/p16/apoptosis. Lineage-specifying master transcription factors therefore contrast with p53/p16 in being enriched in self-replicating glioma cells, reveal a cause-effect relationship between aberrant epigenetic repression of late-lineage programs and malignant self-replication, and point to specific epigenetic targets for noncytotoxic glioma-therapy.


Asunto(s)
Neoplasias Encefálicas , Glioma , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Cromatina , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Glioma/tratamiento farmacológico , Glioma/genética , Glioma/patología , Humanos , Factores de Transcripción/genética , Proteína p53 Supresora de Tumor/genética
4.
Semin Neurol ; 38(1): 5-10, 2018 02.
Artículo en Inglés | MEDLINE | ID: mdl-29548046

RESUMEN

Malignant glioma is a common type of brain tumor that remains largely incurable. Although a definitive cell of origin of gliomas remains elusive, numerous population studies, sequencing efforts, and genetically engineered mouse models have contributed to our understanding of the early events that may lead to gliomagenesis. Herein we summarize our current knowledge on the population epidemiology of gliomas, heritable genetic risk factors, the somatic events that contribute to tumor evolution, and mouse models that have shed light on the glioma cell of origin. Future studies will increase our understanding of the sequence of early events within susceptible cells and their niche that trigger the path to malignant transformation. Such knowledge will allow us to design more effective treatment options to control tumor growth or screening methods for early detection.


Asunto(s)
Neoplasias Encefálicas , Glioma , Animales , Neoplasias Encefálicas/epidemiología , Neoplasias Encefálicas/etiología , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Glioma/epidemiología , Glioma/etiología , Glioma/genética , Glioma/patología , Humanos
5.
Nature ; 483(7390): 479-83, 2012 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-22343889

RESUMEN

Both genome-wide genetic and epigenetic alterations are fundamentally important for the development of cancers, but the interdependence of these aberrations is poorly understood. Glioblastomas and other cancers with the CpG island methylator phenotype (CIMP) constitute a subset of tumours with extensive epigenomic aberrations and a distinct biology. Glioma CIMP (G-CIMP) is a powerful determinant of tumour pathogenicity, but the molecular basis of G-CIMP remains unresolved. Here we show that mutation of a single gene, isocitrate dehydrogenase 1 (IDH1), establishes G-CIMP by remodelling the methylome. This remodelling results in reorganization of the methylome and transcriptome. Examination of the epigenome of a large set of intermediate-grade gliomas demonstrates a distinct G-CIMP phenotype that is highly dependent on the presence of IDH mutation. Introduction of mutant IDH1 into primary human astrocytes alters specific histone marks, induces extensive DNA hypermethylation, and reshapes the methylome in a fashion that mirrors the changes observed in G-CIMP-positive lower-grade gliomas. Furthermore, the epigenomic alterations resulting from mutant IDH1 activate key gene expression programs, characterize G-CIMP-positive proneural glioblastomas but not other glioblastomas, and are predictive of improved survival. Our findings demonstrate that IDH mutation is the molecular basis of CIMP in gliomas, provide a framework for understanding oncogenesis in these gliomas, and highlight the interplay between genomic and epigenomic changes in human cancers.


Asunto(s)
Metilación de ADN/genética , Glioma/genética , Isocitrato Deshidrogenasa/genética , Mutación/genética , Fenotipo , Astrocitos/citología , Astrocitos/metabolismo , Supervivencia Celular/genética , Células Cultivadas , Islas de CpG/genética , Epigénesis Genética , Epigenómica , Regulación de la Expresión Génica , Glioblastoma/genética , Glioblastoma/patología , Glioma/patología , Células HEK293 , Histonas/metabolismo , Humanos , Isocitrato Deshidrogenasa/metabolismo , Metaboloma/genética , Células Tumorales Cultivadas
6.
Nature ; 483(7390): 474-8, 2012 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-22343901

RESUMEN

Recurrent mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 have been identified in gliomas, acute myeloid leukaemias (AML) and chondrosarcomas, and share a novel enzymatic property of producing 2-hydroxyglutarate (2HG) from α-ketoglutarate. Here we report that 2HG-producing IDH mutants can prevent the histone demethylation that is required for lineage-specific progenitor cells to differentiate into terminally differentiated cells. In tumour samples from glioma patients, IDH mutations were associated with a distinct gene expression profile enriched for genes expressed in neural progenitor cells, and this was associated with increased histone methylation. To test whether the ability of IDH mutants to promote histone methylation contributes to a block in cell differentiation in non-transformed cells, we tested the effect of neomorphic IDH mutants on adipocyte differentiation in vitro. Introduction of either mutant IDH or cell-permeable 2HG was associated with repression of the inducible expression of lineage-specific differentiation genes and a block to differentiation. This correlated with a significant increase in repressive histone methylation marks without observable changes in promoter DNA methylation. Gliomas were found to have elevated levels of similar histone repressive marks. Stable transfection of a 2HG-producing mutant IDH into immortalized astrocytes resulted in progressive accumulation of histone methylation. Of the marks examined, increased H3K9 methylation reproducibly preceded a rise in DNA methylation as cells were passaged in culture. Furthermore, we found that the 2HG-inhibitable H3K9 demethylase KDM4C was induced during adipocyte differentiation, and that RNA-interference suppression of KDM4C was sufficient to block differentiation. Together these data demonstrate that 2HG can inhibit histone demethylation and that inhibition of histone demethylation can be sufficient to block the differentiation of non-transformed cells.


Asunto(s)
Diferenciación Celular/genética , Histonas/metabolismo , Isocitrato Deshidrogenasa/genética , Mutación/genética , Células 3T3-L1 , Adipocitos/citología , Adipocitos/efectos de los fármacos , Adipocitos/metabolismo , Animales , Astrocitos/citología , Astrocitos/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Línea Celular Tumoral , Linaje de la Célula/genética , Metilación de ADN/efectos de los fármacos , Inducción Enzimática/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Glioma/enzimología , Glioma/genética , Glioma/patología , Glutaratos/metabolismo , Glutaratos/farmacología , Células HEK293 , Humanos , Isocitrato Deshidrogenasa/antagonistas & inhibidores , Isocitrato Deshidrogenasa/metabolismo , Histona Demetilasas con Dominio de Jumonji/antagonistas & inhibidores , Histona Demetilasas con Dominio de Jumonji/deficiencia , Histona Demetilasas con Dominio de Jumonji/genética , Histona Demetilasas con Dominio de Jumonji/metabolismo , Metilación/efectos de los fármacos , Ratones , Células-Madre Neurales/metabolismo , Regiones Promotoras Genéticas/genética
7.
Acta Neuropathol Commun ; 12(1): 95, 2024 06 14.
Artículo en Inglés | MEDLINE | ID: mdl-38877600

RESUMEN

MYC dysregulation is pivotal in the onset and progression of IDH-mutant gliomas, mostly driven by copy-number alterations, regulatory element alterations, or epigenetic changes. Our pilot analysis uncovered instances of relative MYC overexpression without alterations in the proximal MYC network (PMN), prompting a deeper investigation into potential novel oncogenic mechanisms. Analysing comprehensive genomics profiles of 236 "IDH-mutant 1p/19q non-co-deleted" lower-grade gliomas from The Cancer Genome Atlas, we identified somatic genomic alterations within the PMN. In tumours without PMN-alterations but with MYC-overexpression, genes correlated with MYC-overexpression were identified. Our analyses yielded that 86/236 of astrocytomas exhibited no PMN-alterations, a subset of 21/86 displaying relative MYC overexpression. Within this subset, we discovered 42 genes inversely correlated with relative MYC expression, all on 19q. Further analysis pinpointed a minimal common region at 19q13.43, encompassing 15 genes. The inverse correlations of these 15 genes with relative MYC overexpression were re-confirmed using independent scRNAseq data. Further, the micro-deleted astrocytoma subset displayed significantly higher genomic instability compared to WT cases, but lower instability compared to PMN-hit cases. This newly identified 19q micro-deletion represents a potential novel mechanism underlying MYC dysregulation in astrocytomas. Given the prominence of 19q loss in IDH-mutant gliomas, our findings bear significant implications for understanding gliomagenesis.


Asunto(s)
Astrocitoma , Neoplasias Encefálicas , Deleción Cromosómica , Cromosomas Humanos Par 19 , Isocitrato Deshidrogenasa , Proteínas Proto-Oncogénicas c-myc , Humanos , Isocitrato Deshidrogenasa/genética , Astrocitoma/genética , Astrocitoma/patología , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Cromosomas Humanos Par 19/genética , Mutación
8.
bioRxiv ; 2024 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-38712107

RESUMEN

Mutations in isocitrate dehydrogenase 1 (IDH1) impart a neomorphic reaction that produces the oncometabolite D-2-hydroxyglutarate (D2HG), which can inhibit DNA and histone demethylases to drive tumorigenesis via epigenetic changes. Though heterozygous point mutations in patients primarily affect residue R132, there are myriad D2HG-producing mutants that display unique catalytic efficiency of D2HG production. Here, we show that catalytic efficiency of D2HG production is greater in IDH1 R132Q than R132H mutants, and expression of IDH1 R132Q in cellular and mouse xenograft models leads to higher D2HG concentrations in cells, tumors, and sera compared to R132H-expressing models. Reduced representation bisulfite sequencing (RRBS) analysis of xenograft tumors shows expression of IDH1 R132Q relative to R132H leads to hypermethylation patterns in pathways associated with DNA damage. Transcriptome analysis indicates that the IDH1 R132Q mutation has a more aggressive pro-tumor phenotype, with members of EGFR, Wnt, and PI3K signaling pathways differentially expressed, perhaps through non-epigenetic routes. Together, these data suggest that the catalytic efficiency of IDH1 mutants modulate D2HG levels in cellular and in vivo models, resulting in unique epigenetic and transcriptomic consequences where higher D2HG levels appear to be associated with more aggressive tumors.

9.
Acta Neuropathol Commun ; 11(1): 13, 2023 01 16.
Artículo en Inglés | MEDLINE | ID: mdl-36647117

RESUMEN

Capicua (CIC) is an important downstream molecule of RTK/RAS/MAPK pathway. The regulatory mechanism of CIC underlying tumorigenesis in oligodendroglioma, where CIC is frequently mutated, has yet to be fully elucidated. Using patient-derived glioma lines, RNA-sequencing and bioinformatic analysis of publicly available databases, we investigated how CIC loss- or gain-of-function regulates its downstream targets, cell proliferation and glutamate release. Our results indicate an increased frequency of CIC truncating mutations in oligodendroglioma during progression. In vitro, CIC modulation had a modest effect on cell proliferation in glioma lines, and no significant changes in the expression of ETV1, ETV4 and ETV5. Transcriptional repression of known CIC targets was observed in gliomas expressing non-phosphorylatable CIC variant on Ser173 which was unable to interact with 14-3-3. These data outline a mechanism by which the repressor function of CIC is inhibited by 14-3-3 in gliomas. Using transcriptional profiling, we found that genes related to glutamate release were upregulated because of CIC depletion. In addition, loss of CIC leads to increased extracellular glutamate. Consistent with this, CIC restoration in an oligodendroglioma line reduced the levels of extracellular glutamate, neuronal toxicity and xCT/SLC7A11 expression. Our findings may provide a molecular basis for the prevention of glioma-associated seizures.


Asunto(s)
Sistema de Transporte de Aminoácidos y+ , Glioma , Oligodendroglioma , Proteínas Represoras , Humanos , Sistema de Transporte de Aminoácidos y+/metabolismo , Glioma/genética , Ácido Glutámico , Neuronas/metabolismo , Oligodendroglioma/genética , Proteínas Represoras/genética
10.
Cancers (Basel) ; 15(3)2023 Jan 24.
Artículo en Inglés | MEDLINE | ID: mdl-36765673

RESUMEN

In clinical pharmacology, drug quantification is mainly performed from the circulation for pharmacokinetic purposes. Finely monitoring the chemical effect of drugs at their chemical sites of action for pharmacodynamics would have a major impact in several contexts of personalized medicine. Monitoring appropriate drug exposure is particularly challenging for alkylating drugs such as temozolomide (TMZ) because there is no flow equilibrium that would allow reliable conclusions to be drawn about the alkylation of the target site from plasma concentrations. During the treatment of glioblastoma, it appears, therefore, promising to directly monitor the alkylating effect of TMZ rather than plasma exposure, ideally at the site of action. Mass spectrometry (MS) is a method of choice for the quantification of methylated guanines and, more specifically, of O6-methylguanines as a marker of TMZ exposure at the site of action. Depending on the chosen strategy to analyze modified purines and 2'-deoxynucleosides, the analysis of methylated guanines and 2'-deoxyguanosines is prone to important artefacts due to the overlap between masses of (i) guanines from DNA and RNA, and (ii) different methylated species of guanines. Therefore, the specific analysis of O6-methyl-2'deoxyguanosine, which is the product of the TMZ effect, is highly challenging. In this work, we report observations from matrix-assisted laser desorption/ionization (MALDI), and desorption electrospray ionization (DESI) MS analyses. These allow for the construction of a decision tree to initiate studies using desorption/ionization MS for the analysis of 2'-deoxyguanosine methylations induced by TMZ.

11.
Adv Healthc Mater ; 12(24): e2300591, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37162029

RESUMEN

To address the challenge of drug resistance and limited treatment options for recurrent gliomas with IDH1 mutations, a highly miniaturized screening of 2208 FDA-approved drugs is conducted using a high-throughput droplet microarray (DMA) platform. Two patient-derived temozolomide-resistant tumorspheres harboring endogenous IDH1 mutations (IDH1mut ) are utilized. Screening identifies over 20 drugs, including verteporfin (VP), that significantly affected tumorsphere formation and viability. Proteomics analysis reveals that nuclear pore complex may be a potential VP target, suggesting a new mechanism of action independent of its known effects on YAP1. Knockdown experiments exclude YAP1 as a drug target in tumorspheres. Pathway analysis shows that NUP107 is a potential upstream regulator associated with VP response. Analysis of publicly available genomic datasets shows a significant correlation between high NUP107 expression and decreased survival in IDH1mut astrocytoma, suggesting NUP107 may be a potential biomarker for VP response. This study demonstrates a miniaturized approach for cost-effective drug repurposing using 3D glioma models and identifies nuclear pore complex as a potential target for drug development. The findings provide preclinical evidence to support in vivo and clinical studies of VP and other identified compounds to treat IDH1mut gliomas, which may ultimately improve clinical outcomes for patients with this challenging disease.


Asunto(s)
Neoplasias Encefálicas , Glioma , Humanos , Temozolomida/farmacología , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Reposicionamiento de Medicamentos , Isocitrato Deshidrogenasa/genética , Isocitrato Deshidrogenasa/metabolismo , Isocitrato Deshidrogenasa/uso terapéutico , Glioma/tratamiento farmacológico , Glioma/genética , Glioma/metabolismo
12.
Neuro Oncol ; 25(6): 1031-1043, 2023 06 02.
Artículo en Inglés | MEDLINE | ID: mdl-36215168

RESUMEN

BACKGROUND: IDH mutant gliomas are grouped into astrocytomas or oligodendrogliomas depending on the codeletion of chromosome arms 1p and 19q. Although the genomic alterations of IDH mutant gliomas have been well described, transcriptional changes unique to either tumor type have not been fully understood. Here, we identify Tripartite Motif Containing 67 (TRIM67), an E3 ubiquitin ligase with essential roles during neuronal development, as an oncogene distinctly upregulated in oligodendrogliomas. METHODS: We used several cell lines, including patient-derived oligodendroglioma tumorspheres, to knock down or overexpress TRIM67. We coupled high-throughput assays, including RNA sequencing, total lysate-mass spectrometry (MS), and coimmunoprecipitation (co-IP)-MS with functional assays including immunofluorescence (IF) staining, co-IP, and western blotting (WB) to assess the in vitro phenotype associated with TRIM67. Patient-derived oligodendroglioma tumorspheres were orthotopically implanted in mice to determine the effect of TRIM67 on tumor growth and survival. RESULTS: TRIM67 overexpression alters the abundance of cytoskeletal proteins and induces membrane bleb formation. TRIM67-associated blebbing was reverted with the nonmuscle class II myosin inhibitor blebbistatin and selective ROCK inhibitor fasudil. NOGO-A/Rho GTPase/ROCK2 signaling is altered upon TRIM67 ectopic expression, pointing to the underlying mechanism for TRIM67-induced blebbing. Phenotypically, TRIM67 expression resulted in higher cell motility and reduced cell adherence. In orthotopic implantation models of patient-derived oligodendrogliomas, TRIM67 accelerated tumor growth, reduced overall survival, and led to increased vimentin expression at the tumor margin. CONCLUSIONS: Taken together, our results demonstrate that upregulated TRIM67 induces blebbing-based rounded cell morphology through Rho GTPase/ROCK-mediated signaling thereby contributing to glioma pathogenesis.


Asunto(s)
Astrocitoma , Neoplasias Encefálicas , Glioma , Oligodendroglioma , Animales , Ratones , Humanos , Oligodendroglioma/genética , Proteínas Nogo/genética , Glioma/patología , Astrocitoma/genética , Transformación Celular Neoplásica , Carcinogénesis , Cromosomas Humanos Par 1 , Neoplasias Encefálicas/patología , Cromosomas Humanos Par 19 , Isocitrato Deshidrogenasa/genética , Mutación , Proteínas de Motivos Tripartitos/genética , Proteínas del Citoesqueleto/genética
13.
Cell Rep Med ; 4(11): 101249, 2023 11 21.
Artículo en Inglés | MEDLINE | ID: mdl-37883975

RESUMEN

The isocitrate dehydrogenase (IDH) gene is recurrently mutated in adult diffuse gliomas. IDH-mutant gliomas are categorized into oligodendrogliomas and astrocytomas, each with unique pathological features. Here, we use single-nucleus RNA and ATAC sequencing to compare the molecular heterogeneity of these glioma subtypes. In addition to astrocyte-like, oligodendrocyte progenitor-like, and cycling tumor subpopulations, a tumor population enriched for ribosomal genes and translation elongation factors is primarily present in oligodendrogliomas. Longitudinal analysis of astrocytomas indicates that the proportion of tumor subpopulations remains stable in recurrent tumors. Analysis of tumor-associated microglia/macrophages (TAMs) reveals significant differences between oligodendrogliomas, with astrocytomas harboring inflammatory TAMs expressing phosphorylated STAT1, as confirmed by immunohistochemistry. Furthermore, inferred receptor-ligand interactions between tumor subpopulations and TAMs may contribute to TAM state diversity. Overall, our study sheds light on distinct tumor populations, TAM heterogeneity, TAM-tumor interactions in IDH-mutant glioma subtypes, and the relative stability of tumor subpopulations in recurrent astrocytomas.


Asunto(s)
Astrocitoma , Neoplasias Encefálicas , Glioma , Oligodendroglioma , Humanos , Oligodendroglioma/genética , Oligodendroglioma/patología , Neoplasias Encefálicas/genética , Microglía/patología , Mutación , Recurrencia Local de Neoplasia/genética , Glioma/genética , Glioma/patología , Astrocitoma/genética , Isocitrato Deshidrogenasa/genética
14.
Biomedicines ; 10(2)2022 Jan 19.
Artículo en Inglés | MEDLINE | ID: mdl-35203421

RESUMEN

Epigenetic drugs are used for the clinical treatment of hematologic malignancies; however, their therapeutic potential in solid tumors is still under investigation. Current evidence suggests that epigenetic drugs may lead to antitumor immunity by increasing antigen presentation and may enhance the therapeutic effect of immune checkpoint inhibitors. Here, we highlight their impact on the tumor epigenome and discuss the recent evidence that epigenetic agents may optimize the immune microenvironment and promote antiviral response.

15.
Neoplasia ; 28: 100790, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35398668

RESUMEN

Mutations in IDH1 and IDH2 drive the development of gliomas. These genetic alterations promote tumor cell renewal, disrupt differentiation states, and induce stem-like properties. Understanding how this phenotypic reprogramming occurs remains an area of high interest in glioma research. Previously, we showed that IDH mutation results in the development of a CD24-positive cell population in gliomas. Here, we demonstrate that this CD24-positive population possesses striking stem-like properties at the molecular and phenotypic levels. We found that CD24 expression is associated with stem-like features in IDH-mutant tumors, a patient-derived gliomasphere model, and a neural stem cell model of IDH1-mutant glioma. In orthotopic models, CD24-positive cells display enhanced tumor initiating potency compared to CD24-negative cells. Furthermore, CD24 knockdown results in changes in cell viability, proliferation rate, and gene expression that closely resemble a CD24-negative phenotype. Our data demonstrate that induction of a CD24-positive population is one mechanism by which IDH-mutant tumors acquire stem-like properties. These findings have significant implications for our understanding of the molecular underpinnings of IDH-mutant gliomas.


Asunto(s)
Neoplasias Encefálicas , Glioma , Isocitrato Deshidrogenasa , Células Madre Neoplásicas , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Antígeno CD24/genética , Antígeno CD24/metabolismo , Glioma/genética , Glioma/metabolismo , Glioma/patología , Humanos , Isocitrato Deshidrogenasa/genética , Isocitrato Deshidrogenasa/metabolismo , Mutación , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Fenotipo
16.
Neuro Oncol ; 24(11): 1911-1924, 2022 11 02.
Artículo en Inglés | MEDLINE | ID: mdl-35468210

RESUMEN

BACKGROUND: Glioblastoma (GBM) is an aggressive tumor that frequently exhibits gain of chromosome 7, loss of chromosome 10, and aberrantly activated receptor tyrosine kinase signaling pathways. Previously, we identified Mesenchyme Homeobox 2 (MEOX2), a gene located on chromosome 7, as an upregulated transcription factor in GBM. Overexpressed transcription factors can be involved in driving GBM. Here, we aimed to address the role of MEOX2 in GBM. METHODS: Patient-derived GBM tumorspheres were used to constitutively knockdown or overexpress MEOX2 and subjected to in vitro assays including western blot to assess ERK phosphorylation. Cerebral organoid models were used to investigate the role of MEOX2 in growth initiation. Intracranial mouse implantation models were used to assess the tumorigenic potential of MEOX2. RNA-sequencing, ACT-seq, and CUT&Tag were used to identify MEOX2 target genes. RESULTS: MEOX2 enhanced ERK signaling through a feed-forward mechanism. We identified Ser155 as a putative ERK-dependent phosphorylation site upstream of the homeobox-domain of MEOX2. S155A substitution had a major effect on MEOX2 protein levels and altered its subnuclear localization. MEOX2 overexpression cooperated with p53 and PTEN loss in cerebral organoid models of human malignant gliomas to induce cell proliferation. Using high-throughput genomics, we identified putative transcriptional target genes of MEOX2 in patient-derived GBM tumorsphere models and a fresh frozen GBM tumor. CONCLUSIONS: We identified MEOX2 as an oncogenic transcription regulator in GBM. MEOX2 increases proliferation in cerebral organoid models of GBM and feeds into ERK signaling that represents a core signaling pathway in GBM.


Asunto(s)
Glioblastoma , Glioma , Ratones , Animales , Humanos , Genes Homeobox , Proteínas de Homeodominio/genética , Glioma/genética , Glioblastoma/patología , Proliferación Celular , Factores de Transcripción/genética , Carcinogénesis/genética , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica
17.
18.
Cancers (Basel) ; 13(8)2021 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-33920839

RESUMEN

Although our understanding of the two-dimensional state of brain tumors has greatly expanded, relatively little is known about their spatial structures. The interactions between tumor cells and the tumor microenvironment (TME) occur in a three-dimensional (3D) space. This volumetric distribution is important for elucidating tumor biology and predicting and monitoring response to therapy. While static 2D imaging modalities have been critical to our understanding of these tumors, studies using 3D imaging modalities are needed to understand how malignant cells co-opt the host brain. Here we summarize the preclinical utility of in vivo imaging using two-photon microscopy in brain tumors and present ex vivo approaches (light-sheet fluorescence microscopy and serial two-photon tomography) and highlight their current and potential utility in neuro-oncology using data from solid tumors or pathological brain as examples.

19.
Neuro Oncol ; 23(1): 76-87, 2021 01 30.
Artículo en Inglés | MEDLINE | ID: mdl-32882013

RESUMEN

BACKGROUND: Decitabine (DAC) is an FDA-approved DNA methyltransferase (DNMT) inhibitor that is used in the treatment of patients with myelodysplastic syndromes. Previously, we showed that DAC marks antitumor activity against gliomas with isocitrate dehydrogenase 1 (IDH1) mutations. Based on promising preclinical results, a clinical trial has been launched to determine the effect of DAC in IDH-mutant gliomas. The next step is to comprehensively assess the efficacy and potential determinants of response to DAC in malignant gliomas. METHODS: The expression and activity of telomerase reverse transcriptase (TERT) and DNMT1 were manipulated in patient-derived IDH1-mutant and -wildtype glioma lines, followed by assessment of cell proliferation with DAC treatment alone or in combination with telomerase inhibitors. RNA sequencing, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, and correlation analysis were performed. RESULTS: IDH1-mutant glioma tumorspheres with hemizygous codeletion of chromosome arms 1p/19q were particularly sensitive to DAC and showed significant inhibition of DNA replication genes. Our transcriptome analysis revealed that DAC induced expression of cyclin-dependent kinase inhibitor 1A/p21 (CDKN1A), along with downregulation of TERT. These molecular changes were also observed following doxorubicin treatment, supporting the importance of DAC-induced DNA damage in contributing to this effect. We demonstrated that knockdown of p21 led to TERT upregulation. Strikingly, TERT overexpression increased DNMT1 levels and DAC sensitivity via a telomerase-independent mechanism. Furthermore, RNA inhibition (RNAi) targeting of DNMT1 abrogated DAC response in TERT-proficient glioma cells. CONCLUSIONS: DAC downregulates TERT through p21 induction. Our data point to TERT and DNMT1 levels as potential determinants of response to DAC treatment.


Asunto(s)
Neoplasias Encefálicas , Glioma , Telomerasa , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Decitabina/farmacología , Glioma/tratamiento farmacológico , Glioma/genética , Humanos , Isocitrato Deshidrogenasa/genética , Isocitrato Deshidrogenasa/metabolismo , Mutación , Regiones Promotoras Genéticas , Telomerasa/genética
20.
Biomedicines ; 10(1)2021 Dec 21.
Artículo en Inglés | MEDLINE | ID: mdl-35052681

RESUMEN

Temozolomide (TMZ), together with bulk resection and focal radiotherapy, is currently a standard of care for glioblastoma. Absorption, distribution, metabolism, and excretion (ADME) parameters, together with the mode of action of TMZ, make its biochemical and biological action difficult to understand. Accurate understanding of the mode of action of TMZ and the monitoring of TMZ at its anatomical, cellular, and molecular sites of action (SOAs) would greatly benefit precision medicine and the development of novel therapeutic approaches in combination with TMZ. In the present perspective article, we summarize the known ADME parameters and modes of action of TMZ, and we review the possible methodological options to monitor TMZ at its SOAs. We focus our descriptions of methodologies on mass spectrometry-based approaches, and all related considerations are taken into account regarding the avoidance of artifacts in mass spectrometric analysis during sampling, sample preparation, and the evaluation of results. Finally, we provide an overview of potential applications for precision medicine and drug development.

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