RESUMEN
Medulloblastoma is an aggressive brain tumor that occurs predominantly in children. Despite intensive therapy, many patients die of the disease, and novel therapies are desperately needed. Although immunotherapy has shown promise in many cancers, the low mutational burden, limited infiltration of immune effector cells, and immune-suppressive microenvironment of medulloblastoma have led to the assumption that it is unlikely to respond to immunotherapy. However, emerging evidence is challenging this view. Here we review recent preclinical and clinical studies that have identified mechanisms of immune evasion in medulloblastoma, and highlight possible therapeutic interventions that may give new hope to medulloblastoma patients and their families.
Asunto(s)
Neoplasias Encefálicas , Neoplasias Cerebelosas , Meduloblastoma , Neoplasias Cerebelosas/genética , Neoplasias Cerebelosas/terapia , Niño , Humanos , Inmunoterapia , Meduloblastoma/terapia , Microambiente TumoralRESUMEN
Brain tumors are the leading cause of cancer-related death in children, and medulloblastoma (MB) is the most common malignant pediatric brain tumor. Advances in surgery, radiation, and chemotherapy have improved the survival of MB patients. But despite these advances, 25-30% of patients still die from the disease, and survivors suffer severe long-term side effects from the aggressive therapies they receive. Although MB is often considered a single disease, molecular profiling has revealed a significant degree of heterogeneity, and there is a growing consensus that MB consists of multiple subgroups with distinct driver mutations, cells of origin, and prognosis. Here, we review recent progress in MB research, with a focus on the genes and pathways that drive tumorigenesis, the animal models that have been developed to study tumor biology, and the advances in conventional and targeted therapy.
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Neoplasias Cerebelosas , Meduloblastoma , Terapia Molecular Dirigida/métodos , Animales , Neoplasias Cerebelosas/clasificación , Neoplasias Cerebelosas/genética , Neoplasias Cerebelosas/terapia , Humanos , Meduloblastoma/clasificación , Meduloblastoma/genética , Meduloblastoma/terapiaRESUMEN
Medulloblastoma is a malignant childhood cerebellar tumour type that comprises distinct molecular subgroups. Whereas genomic characteristics of these subgroups are well defined, the extent to which cellular diversity underlies their divergent biology and clinical behaviour remains largely unexplored. Here we used single-cell transcriptomics to investigate intra- and intertumoral heterogeneity in 25 medulloblastomas spanning all molecular subgroups. WNT, SHH and Group 3 tumours comprised subgroup-specific undifferentiated and differentiated neuronal-like malignant populations, whereas Group 4 tumours consisted exclusively of differentiated neuronal-like neoplastic cells. SHH tumours closely resembled granule neurons of varying differentiation states that correlated with patient age. Group 3 and Group 4 tumours exhibited a developmental trajectory from primitive progenitor-like to more mature neuronal-like cells, the relative proportions of which distinguished these subgroups. Cross-species transcriptomics defined distinct glutamatergic populations as putative cells-of-origin for SHH and Group 4 subtypes. Collectively, these data provide insights into the cellular and developmental states underlying subtype-specific medulloblastoma biology.
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Genómica , Meduloblastoma/genética , Meduloblastoma/patología , Análisis de la Célula Individual , Transcriptoma , Adolescente , Adulto , Animales , Linaje de la Célula , Cerebelo/metabolismo , Cerebelo/patología , Niño , Preescolar , Variaciones en el Número de Copia de ADN , Regulación Neoplásica de la Expresión Génica , Ácido Glutámico/metabolismo , Humanos , Lactante , Meduloblastoma/clasificación , Ratones , Neuronas/metabolismo , Neuronas/patologíaRESUMEN
Detection of tumor progression in patients with glioblastoma remains a major challenge. Extracellular vesicles (EVs) are potential biomarkers and can be detected in the blood of patients with glioblastoma. In our study, we evaluated the potential of serum-derived EVs from glioblastoma patients to serve as biomarker for tumor progression. EVs from serum of glioblastoma patients and healthy volunteers were separated by size exclusion chromatography and ultracentrifugation. EV markers were defined by using a proximity-extension assay and bead-based flow cytometry. Tumor progression was defined according to modified RANO criteria. EVs from the serum of glioblastoma patients (n = 67) showed an upregulation of CD29, CD44, CD81, CD146, C1QA and histone H3 as compared to serum EVs from healthy volunteers (P value range: <.0001 to .08). For two independent cohorts of glioblastoma patients, we noted upregulation of C1QA, CD44 and histone H3 upon tumor progression, but not in patients with stable disease. In a multivariable logistic regression analysis, a combination of CD29, CD44, CD81, C1QA and histone H3 correlated with RANO-defined tumor progression with an AUC of 0.76. Measurement of CD29, CD44, CD81, C1QA and histone H3 in serum-derived EVs of glioblastoma patients, along with standard MRI assessment, has the potential to improve detection of true tumor progression and thus could be a useful biomarker for clinical decision making.
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Vesículas Extracelulares , Glioblastoma , Humanos , Histonas , Proteínas Sanguíneas , Integrina beta1RESUMEN
Achieving adequate exposure of the free therapeutic agent at the target is a critical determinant of efficacious chemotherapy. With this in mind, a major challenge in developing therapies for central nervous system (CNS) tumors is to overcome barriers to delivery, including the blood-brain barrier (BBB). Panobinostat is a nonselective pan-histone deacetylase inhibitor that is being tested in preclinical and clinical studies, including for the treatment of pediatric medulloblastoma, which has a propensity for leptomeningeal spread and diffuse midline glioma, which can infiltrate into supratentorial brain regions. In this study, we examined the rate, extent, and spatial heterogeneity of panobinostat CNS distribution in mice. Transporter-deficient mouse studies show that panobinostat is a dual substrate of P-glycoprotein (P-gp) and breast cancer resistant protein (Bcrp), which are major efflux transporters expressed at the BBB. The CNS delivery of panobinostat was moderately limited by P-gp and Bcrp, and the unbound tissue-to-plasma partition coefficient of panobinostat was 0.32 and 0.21 in the brain and spinal cord in wild-type mice. In addition, following intravenous administration, panobinostat demonstrated heterogeneous distribution among brain regions, indicating that its efficacy would be influenced by tumor location or the presence and extent of leptomeningeal spread. Simulation using a compartmental BBB model suggests inadequate exposure of free panobinostat in the brain following a recommended oral dosing regimen in patients. Therefore, alternative approaches to CNS delivery may be necessary to have adequate exposure of free panobinostat for the treatment of a broad range of pediatric brain tumors. SIGNIFICANCE STATEMENT: This study shows that the central nervous system (CNS) penetration of panobinostat is limited by P-gp and Bcrp, and its efficacy may be limited by inadequate distribution to the tumor. Panobinostat has heterogeneous distribution into various brain regions, indicating that its efficacy might depend on the anatomical location of the tumors. These distributional parameters in the mouse CNS can inform both preclinical and clinical trial study design and may guide treatment for these devastating brain tumors in children.
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Transportadoras de Casetes de Unión a ATP , Neoplasias Encefálicas , Niño , Humanos , Animales , Ratones , Panobinostat/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Proteínas de Neoplasias/metabolismo , Sistema Nervioso Central/metabolismo , Encéfalo/metabolismo , Barrera Hematoencefálica/metabolismo , Neoplasias Encefálicas/metabolismo , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Proteínas de Transporte de Membrana/metabolismoRESUMEN
Leukemias bearing fusions of the AF10/MLLT10 gene are associated with poor prognosis, and therapies targeting these fusion proteins (FPs) are lacking. To understand mechanisms underlying AF10 fusion-mediated leukemogenesis, we generated inducible mouse models of acute myeloid leukemia (AML) driven by the most common AF10 FPs, PICALM/CALM-AF10 and KMT2A/MLL-AF10, and performed comprehensive characterization of the disease using transcriptomic, epigenomic, proteomic, and functional genomic approaches. Our studies provide a detailed map of gene networks and protein interactors associated with key AF10 fusions involved in leukemia. Specifically, we report that AF10 fusions activate a cascade of JAK/STAT-mediated inflammatory signaling through direct recruitment of JAK1 kinase. Inhibition of the JAK/STAT signaling by genetic Jak1 deletion or through pharmacological JAK/STAT inhibition elicited potent antioncogenic effects in mouse and human models of AF10 fusion AML. Collectively, our study identifies JAK1 as a tractable therapeutic target in AF10-rearranged leukemias.
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Carcinogénesis , Reordenamiento Génico , Quinasas Janus , Sistema de Señalización de MAP Quinasas/genética , Proteínas de Neoplasias , Factores de Transcripción STAT , Factores de Transcripción , Animales , Carcinogénesis/genética , Carcinogénesis/metabolismo , Femenino , Humanos , Quinasas Janus/genética , Quinasas Janus/metabolismo , Ratones , Ratones Endogámicos NOD , Ratones SCID , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Factores de Transcripción STAT/genética , Factores de Transcripción STAT/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Células U937RESUMEN
Human cells have twenty-three pairs of chromosomes. In cancer, however, genes can be amplified in chromosomes or in circular extrachromosomal DNA (ecDNA), although the frequency and functional importance of ecDNA are not understood. We performed whole-genome sequencing, structural modelling and cytogenetic analyses of 17 different cancer types, including analysis of the structure and function of chromosomes during metaphase of 2,572 dividing cells, and developed a software package called ECdetect to conduct unbiased, integrated ecDNA detection and analysis. Here we show that ecDNA was found in nearly half of human cancers; its frequency varied by tumour type, but it was almost never found in normal cells. Driver oncogenes were amplified most commonly in ecDNA, thereby increasing transcript level. Mathematical modelling predicted that ecDNA amplification would increase oncogene copy number and intratumoural heterogeneity more effectively than chromosomal amplification. We validated these predictions by quantitative analyses of cancer samples. The results presented here suggest that ecDNA contributes to accelerated evolution in cancer.
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Variaciones en el Número de Copia de ADN/genética , Evolución Molecular , Amplificación de Genes/genética , Heterogeneidad Genética , Modelos Genéticos , Neoplasias/genética , Oncogenes/genética , Cromosomas Humanos/genética , Análisis Citogenético , Análisis Mutacional de ADN , Genoma Humano/genética , Humanos , Metafase/genética , Neoplasias/clasificación , ARN Mensajero/análisis , ARN Neoplásico/genética , Reproducibilidad de los Resultados , Programas InformáticosRESUMEN
Medulloblastoma (MB) is the most common malignant pediatric brain tumor. MB is classified into four primary molecular subgroups: wingless (WNT), sonic hedgehog (SHH), Group 3 (G3), and Group 4 (G4), and further genomic and proteomic subtypes have been reported. Subgroup heterogeneity and few actionable mutations have hindered the development of targeted therapies, especially for G3 MB, which has a particularly poor prognosis. To identify novel therapeutic targets for MB, we performed mass spectrometry-based deep expression proteomics and phosphoproteomics in 20 orthotopic patient-derived xenograft (PDX) models of MB comprising SHH, G3, and G4 subgroups. We found that the proteomic profiles of MB PDX tumors are closely aligned with those of primary human MB tumors illustrating the utility of PDX models. SHH PDXs were enriched for NFκB and p38 MAPK signaling, while G3 PDXs were characterized by MYC activity. Additionally, we found a significant association between actinomycin D sensitivity and increased abundance of MYC and MYC target genes. Our results highlight several candidate pathways that may serve as targets for new MB therapies. Mass spectrometry data are available via ProteomeXchange with identifier PXD035070.
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Neoplasias Encefálicas , Neoplasias Cerebelosas , Meduloblastoma , Animales , Neoplasias Encefálicas/genética , Neoplasias Cerebelosas/genética , Neoplasias Cerebelosas/metabolismo , Neoplasias Cerebelosas/patología , Niño , Modelos Animales de Enfermedad , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Proteínas Hedgehog/uso terapéutico , Xenoinjertos , Humanos , Meduloblastoma/genética , Meduloblastoma/metabolismo , Meduloblastoma/patología , ProteómicaRESUMEN
Epigenetic alterations, that is, disruption of DNA methylation and chromatin architecture, are now acknowledged as a universal feature of tumorigenesis. Medulloblastoma, a clinically challenging, malignant childhood brain tumour, is no exception. Despite much progress from recent genomics studies, with recurrent changes identified in each of the four distinct tumour subgroups (WNT-pathway-activated, SHH-pathway-activated, and the less-well-characterized Group 3 and Group 4), many cases still lack an obvious genetic driver. Here we present whole-genome bisulphite-sequencing data from thirty-four human and five murine tumours plus eight human and three murine normal controls, augmented with matched whole-genome, RNA and chromatin immunoprecipitation sequencing data. This comprehensive data set allowed us to decipher several features underlying the interplay between the genome, epigenome and transcriptome, and its effects on medulloblastoma pathophysiology. Most notable were highly prevalent regions of hypomethylation correlating with increased gene expression, extending tens of kilobases downstream of transcription start sites. Focal regions of low methylation linked to transcription-factor-binding sites shed light on differential transcriptional networks between subgroups, whereas increased methylation due to re-normalization of repressed chromatin in DNA methylation valleys was positively correlated with gene expression. Large, partially methylated domains affecting up to one-third of the genome showed increased mutation rates and gene silencing in a subgroup-specific fashion. Epigenetic alterations also affected novel medulloblastoma candidate genes (for example, LIN28B), resulting in alternative promoter usage and/or differential messenger RNA/microRNA expression. Analysis of mouse medulloblastoma and precursor-cell methylation demonstrated a somatic origin for many alterations. Our data provide insights into the epigenetic regulation of transcription and genome organization in medulloblastoma pathogenesis, which are probably also of importance in a wider developmental and disease context.
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Metilación de ADN/genética , Regulación Neoplásica de la Expresión Génica , Silenciador del Gen , Meduloblastoma/genética , Análisis de Secuencia de ADN/métodos , Animales , Sitios de Unión , Línea Celular Tumoral , Cromatina/genética , Cromatina/metabolismo , Inmunoprecipitación de Cromatina , Femenino , Genoma/genética , Histonas/metabolismo , Humanos , Meduloblastoma/patología , Ratones , Regiones Promotoras Genéticas/genética , Proteínas de Unión al ARN/genética , Factores de Transcripción/metabolismo , Transcripción GenéticaRESUMEN
Medulloblastoma, the most common malignant paediatric brain tumour, is currently treated with nonspecific cytotoxic therapies including surgery, whole-brain radiation, and aggressive chemotherapy. As medulloblastoma exhibits marked intertumoural heterogeneity, with at least four distinct molecular variants, previous attempts to identify targets for therapy have been underpowered because of small samples sizes. Here we report somatic copy number aberrations (SCNAs) in 1,087 unique medulloblastomas. SCNAs are common in medulloblastoma, and are predominantly subgroup-enriched. The most common region of focal copy number gain is a tandem duplication of SNCAIP, a gene associated with Parkinson's disease, which is exquisitely restricted to Group 4α. Recurrent translocations of PVT1, including PVT1-MYC and PVT1-NDRG1, that arise through chromothripsis are restricted to Group 3. Numerous targetable SCNAs, including recurrent events targeting TGF-ß signalling in Group 3, and NF-κB signalling in Group 4, suggest future avenues for rational, targeted therapy.
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Neoplasias Cerebelosas/clasificación , Neoplasias Cerebelosas/genética , Genoma Humano/genética , Variación Estructural del Genoma/genética , Meduloblastoma/clasificación , Meduloblastoma/genética , Proteínas Portadoras/genética , Neoplasias Cerebelosas/metabolismo , Niño , Variaciones en el Número de Copia de ADN/genética , Duplicación de Gen/genética , Genes myc/genética , Genómica , Proteínas Hedgehog/metabolismo , Humanos , Meduloblastoma/metabolismo , FN-kappa B/metabolismo , Proteínas del Tejido Nervioso/genética , Proteínas de Fusión Oncogénica/genética , Proteínas/genética , ARN Largo no Codificante , Transducción de Señal , Factor de Crecimiento Transformador beta/metabolismo , Translocación Genética/genéticaRESUMEN
The rhombic lip gives rise to neuronal populations that contribute to cerebellar, proprioceptive and interoceptive networks. Cell production depends on the expression of the basic helix-loop-helix (bHLH) transcription factor Atoh1. In rhombomere 1, Atoh1-positive cells give rise to both cerebellar neurons and extra-cerebellar nuclei in ventral hindbrain. The origin of this cellular diversity has previously been attributed to temporal signals rather than spatial patterning. Here, we show that in both chick and mouse the cerebellar Atoh1 precursor pool is partitioned into initially cryptic spatial domains that reflect the activity of two different organisers: an isthmic Atoh1 domain, which gives rise to isthmic nuclei, and the rhombic lip, which generates deep cerebellar nuclei and granule cells. We use a combination of in vitro explant culture, genetic fate mapping and gene overexpression and knockdown to explore the role of isthmic signalling in patterning these domains. We show that an FGF-dependent isthmic Atoh1 domain is the origin of distinct populations of Lhx9-positive neurons in the extra-cerebellar isthmic nuclei. In the cerebellum, ectopic FGF induces proliferation while blockade reduces the length of the cerebellar rhombic lip. FGF signalling is not required for the specification of cerebellar cell types from the rhombic lip and its upregulation inhibits their production. This suggests that although the isthmus regulates the size of the cerebellar anlage, the downregulation of isthmic FGF signals is required for induction of rhombic lip-derived cerebellar neurons.
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Proteínas Aviares/química , Proteínas Aviares/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Cerebelo/embriología , Cerebelo/metabolismo , Animales , Proteínas Aviares/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Embrión de Pollo , Femenino , Factor 8 de Crecimiento de Fibroblastos/genética , Factor 8 de Crecimiento de Fibroblastos/metabolismo , Regulación del Desarrollo de la Expresión Génica , Técnicas de Silenciamiento del Gen , Proteínas con Homeodominio LIM/genética , Proteínas con Homeodominio LIM/metabolismo , Mesencéfalo/embriología , Mesencéfalo/metabolismo , Ratones , Ratones Noqueados , Ratones Mutantes , Factores de Transcripción Otx/genética , Factores de Transcripción Otx/metabolismo , Embarazo , Rombencéfalo/embriología , Rombencéfalo/metabolismo , Transducción de Señal , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
Studying the early stages of cancer can provide important insight into the molecular basis of the disease. We identified a preneoplastic stage in the patched (ptc) mutant mouse, a model for the brain tumor medulloblastoma. Preneoplastic cells (PNCs) are found in most ptc mutants during early adulthood, but only 15% of these animals develop tumors. Although PNCs are found in mice that develop tumors, the ability of PNCs to give rise to tumors has never been demonstrated directly, and the fate of cells that do not form tumors remains unknown. Using genetic fate mapping and orthotopic transplantation, we provide definitive evidence that PNCs give rise to tumors, and show that the predominant fate of PNCs that do not form tumors is differentiation. Moreover, we show that N-myc, a gene commonly amplified in medulloblastoma, can dramatically alter the fate of PNCs, preventing differentiation and driving progression to tumors. Importantly, N-myc allows PNCs to grow independently of hedgehog signaling, making the resulting tumors resistant to hedgehog antagonists. These studies provide the first direct evidence that PNCs can give rise to tumors, and demonstrate that identification of genetic changes that promote tumor progression is critical for designing effective therapies for cancer.
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Diferenciación Celular/fisiología , Meduloblastoma/patología , Lesiones Precancerosas/patología , Proteínas Proto-Oncogénicas c-myc/metabolismo , Animales , Movimiento Celular , Proliferación Celular , Cerebelo/citología , Modelos Animales de Enfermedad , Expresión Génica , Genes Reporteros , Proteínas Hedgehog/antagonistas & inhibidores , Ratones , Ratones SCID , Ratones Transgénicos , Células Madre/citología , Células Madre/efectos de los fármacos , Alcaloides de Veratrum/farmacologíaRESUMEN
Medulloblastoma encompasses a collection of clinically and molecularly diverse tumour subtypes that together comprise the most common malignant childhood brain tumour. These tumours are thought to arise within the cerebellum, with approximately 25% originating from granule neuron precursor cells (GNPCs) after aberrant activation of the Sonic Hedgehog pathway (hereafter, SHH subtype). The pathological processes that drive heterogeneity among the other medulloblastoma subtypes are not known, hindering the development of much needed new therapies. Here we provide evidence that a discrete subtype of medulloblastoma that contains activating mutations in the WNT pathway effector CTNNB1 (hereafter, WNT subtype) arises outside the cerebellum from cells of the dorsal brainstem. We found that genes marking human WNT-subtype medulloblastomas are more frequently expressed in the lower rhombic lip (LRL) and embryonic dorsal brainstem than in the upper rhombic lip (URL) and developing cerebellum. Magnetic resonance imaging (MRI) and intra-operative reports showed that human WNT-subtype tumours infiltrate the dorsal brainstem, whereas SHH-subtype tumours are located within the cerebellar hemispheres. Activating mutations in Ctnnb1 had little impact on progenitor cell populations in the cerebellum, but caused the abnormal accumulation of cells on the embryonic dorsal brainstem which included aberrantly proliferating Zic1(+) precursor cells. These lesions persisted in all mutant adult mice; moreover, in 15% of cases in which Tp53 was concurrently deleted, they progressed to form medulloblastomas that recapitulated the anatomy and gene expression profiles of human WNT-subtype medulloblastoma. We provide the first evidence, to our knowledge, that subtypes of medulloblastoma have distinct cellular origins. Our data provide an explanation for the marked molecular and clinical differences between SHH- and WNT-subtype medulloblastomas and have profound implications for future research and treatment of this important childhood cancer.
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Tronco Encefálico/patología , Neoplasias Cerebelosas/patología , Meduloblastoma/patología , Animales , Modelos Animales de Enfermedad , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Ratones , Ratones Transgénicos , Mutación , beta Catenina/genéticaRESUMEN
The WNT pathway plays multiple roles in neural development and is crucial for establishment of the embryonic cerebellum. In addition, WNT pathway mutations are associated with medulloblastoma, the most common malignant brain tumor in children. However, the cell types within the cerebellum that are responsive to WNT signaling remain unknown. Here we investigate the effects of canonical WNT signaling on two important classes of progenitors in the developing cerebellum: multipotent neural stem cells (NSCs) and granule neuron precursors (GNPs). We show that WNT pathway activation in vitro promotes proliferation of NSCs but not GNPs. Moreover, mice that express activated ß-catenin in the cerebellar ventricular zone exhibit increased proliferation of NSCs in that region, whereas expression of the same protein in GNPs impairs proliferation. Although ß-catenin-expressing NSCs proliferate they do not undergo prolonged expansion or neoplastic growth; rather, WNT signaling markedly interferes with their capacity for self-renewal and differentiation. At a molecular level, mutant NSCs exhibit increased expression of c-Myc, which might account for their transient proliferation, but also express high levels of bone morphogenetic proteins and the cyclin-dependent kinase inhibitor p21, which might contribute to their altered self-renewal and differentiation. These studies suggest that the WNT pathway is a potent regulator of cerebellar stem cell growth and differentiation.
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Cerebelo/citología , Cerebelo/metabolismo , Células-Madre Neurales/citología , Células-Madre Neurales/metabolismo , Vía de Señalización Wnt/fisiología , Animales , Diferenciación Celular/genética , Diferenciación Celular/fisiología , Proliferación Celular , Células Cultivadas , Cerebelo/embriología , Citometría de Flujo , Ratones , Reacción en Cadena en Tiempo Real de la Polimerasa , Vía de Señalización Wnt/genética , beta Catenina/genética , beta Catenina/metabolismoRESUMEN
Cancer stem cells (CSCs) are thought to be critical for initiation and propagation of many types of cancer. Because these cells are resistant to conventional therapies, they have been very difficult to eliminate. A study in this issue of Cancer Cell suggests that brain tumor CSCs live in a "vascular niche" that promotes their long-term growth and self-renewal. Disrupting this niche impairs CSC self-renewal and thereby significantly inhibits the growth of tumors. Targeting the unique microenvironment of CSCs may be the key to effective cancer therapy.
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Neoplasias Encefálicas/irrigación sanguínea , Células Madre Neoplásicas , Neovascularización Patológica , Animales , Neoplasias Encefálicas/patología , Humanos , Neuronas/patologíaRESUMEN
Diffuse intrinsic pontine glioma (DIPG) is a devastating brain tumor with a need for novel therapies. So far, monotherapies have failed to prolong survival for these patients, and combinatorial strategies have often shown severe, dose-limiting toxicities. In this issue of the JCI, Duchatel, Jackson, and colleagues address this challenge by introducing a drug combination that mitigates side effects and overcomes resistance. After identifying the PI3K/mTOR pathway as a therapeutic vulnerability, they treated DIPG-bearing mice with paxalisib and saw responses but also observed hyperglycemia as a severe side effect. Combining paxalisib with metformin mitigated this toxicity, but also upregulated protein kinase C (PKC) signaling. To tackle this mechanism of resistance, the authors added the PKC inhibitor enzastaurin to their drug combination and showed that this triple therapy led to improved survival. This approach paves the way for improved outcomes for patients with DIPG and other brain tumors.
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Neoplasias del Tronco Encefálico , Glioma , Metformina , Humanos , Ratones , Animales , Neoplasias del Tronco Encefálico/terapia , Glioma/metabolismo , Metformina/farmacología , Metformina/uso terapéutico , Transducción de Señal , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Combinación de MedicamentosRESUMEN
Recent studies suggest that long non-coding RNAs (lncRNAs) contribute to medulloblastoma (MB) formation and progression. We have identified an lncRNA, lnc-HLX-2-7, as a potential therapeutic target in group 3 (G3) MBs. lnc-HLX-2-7 RNA specifically accumulates in the promoter region of HLX, a sense-overlapping gene of lnc-HLX-2-7, which activates HLX expression by recruiting multiple factors, including enhancer elements. RNA sequencing and chromatin immunoprecipitation reveal that HLX binds to and activates the promoters of several oncogenes, including TBX2, LIN9, HOXM1, and MYC. Intravenous treatment with cerium-oxide-nanoparticle-coated antisense oligonucleotides targeting lnc-HLX-2-7 (CNP-lnc-HLX-2-7) inhibits tumor growth by 40%-50% in an intracranial MB xenograft mouse model. Combining CNP-lnc-HLX-2-7 with standard-of-care cisplatin further inhibits tumor growth and significantly prolongs mouse survival compared with CNP-lnc-HLX-2-7 monotherapy. Thus, the lnc-HLX-2-7-HLX-MYC axis is important for regulating G3 MB progression, providing a strong rationale for using lnc-HLX-2-7 as a therapeutic target for G3 MBs.
Asunto(s)
Neoplasias Cerebelosas , Meduloblastoma , ARN Largo no Codificante , Humanos , Ratones , Animales , Retroalimentación , Meduloblastoma/genética , Meduloblastoma/patología , Oncogenes , Neoplasias Cerebelosas/tratamiento farmacológico , Neoplasias Cerebelosas/genética , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Línea Celular Tumoral , Factores de Transcripción/metabolismo , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismoRESUMEN
Hypothyroidism is commonly detected in patients with medulloblastoma (MB). A possible link between thyroid hormone (TH) signaling and MB pathogenicity has not been reported. Here, we find that TH plays a critical role in promoting tumor cell differentiation. Reduction in TH levels frees the TH receptor, TRα1, to bind to EZH2 and repress expression of NeuroD1, a transcription factor that drives tumor cell differentiation. Increased TH reverses EZH2-mediated repression of NeuroD1 by abrogating the binding of EZH2 and TRα1, thereby stimulating tumor cell differentiation and reducing MB growth. Importantly, TH-induced differentiation of tumor cells is not restricted by the molecular subgroup of MB. These findings establish an unprecedented association between TH signaling and MB pathogenicity, providing solid evidence for TH as a promising modality for MB treatment.
RESUMEN
Hypothyroidism is commonly detected in patients with medulloblastoma (MB). However, whether thyroid hormone (TH) contributes to MB pathogenicity remains undetermined. Here, we find that TH plays a critical role in promoting tumor cell differentiation. Reduction in TH levels frees the TH receptor, TRα1, to bind to EZH2 and repress expression of NeuroD1, a transcription factor that drives tumor cell differentiation. Increased TH reverses EZH2-mediated repression of NeuroD1 by abrogating the binding of EZH2 and TRα1, thereby stimulating tumor cell differentiation and reducing MB growth. Importantly, TH-induced differentiation of tumor cells is not restricted by the molecular subgroup of MB, suggesting that TH can be used to broadly treat MB subgroups. These findings establish an unprecedented association between TH signaling and MB pathogenicity, providing solid evidence for TH as a promising modality for MB treatment.
Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Diferenciación Celular , Proteína Potenciadora del Homólogo Zeste 2 , Meduloblastoma , Hormonas Tiroideas , Meduloblastoma/patología , Meduloblastoma/metabolismo , Meduloblastoma/genética , Humanos , Diferenciación Celular/efectos de los fármacos , Animales , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Proteína Potenciadora del Homólogo Zeste 2/genética , Ratones , Hormonas Tiroideas/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Neoplasias Cerebelosas/patología , Neoplasias Cerebelosas/metabolismo , Neoplasias Cerebelosas/genética , Neoplasias Cerebelosas/tratamiento farmacológico , Línea Celular Tumoral , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Receptores alfa de Hormona Tiroidea/metabolismo , Receptores alfa de Hormona Tiroidea/genética , Transducción de Señal/efectos de los fármacosRESUMEN
Diffuse Midline Gliomas (DMGs) are universally fatal, primarily pediatric malignancies affecting the midline structures of the central nervous system. Despite decades of clinical trials, treatment remains limited to palliative radiation therapy. A major challenge is the coexistence of molecularly distinct malignant cell states with potentially orthogonal drug sensitivities. To address this challenge, we leveraged established network-based methodologies to elucidate Master Regulator (MR) proteins representing mechanistic, non-oncogene dependencies of seven coexisting subpopulations identified by single-cell analysis-whose enrichment in essential genes was validated by pooled CRISPR/Cas9 screens. Perturbational profiles of 372 clinically relevant drugs helped identify those able to invert the activity of subpopulation-specific MRs for follow-up in vivo validation. While individual drugs predicted to target individual subpopulations-including avapritinib, larotrectinib, and ruxolitinib-produced only modest tumor growth reduction in orthotopic models, systemic co-administration induced significant survival extension, making this approach a valuable contribution to the rational design of combination therapy.