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1.
Cell ; 172(5): 1050-1062.e14, 2018 02 22.
Artículo en Inglés | MEDLINE | ID: mdl-29474906

RESUMEN

While the preponderance of morbidity and mortality in medulloblastoma patients are due to metastatic disease, most research focuses on the primary tumor due to a dearth of metastatic tissue samples and model systems. Medulloblastoma metastases are found almost exclusively on the leptomeningeal surface of the brain and spinal cord; dissemination is therefore thought to occur through shedding of primary tumor cells into the cerebrospinal fluid followed by distal re-implantation on the leptomeninges. We present evidence for medulloblastoma circulating tumor cells (CTCs) in therapy-naive patients and demonstrate in vivo, through flank xenografting and parabiosis, that medulloblastoma CTCs can spread through the blood to the leptomeningeal space to form leptomeningeal metastases. Medulloblastoma leptomeningeal metastases express high levels of the chemokine CCL2, and expression of CCL2 in medulloblastoma in vivo is sufficient to drive leptomeningeal dissemination. Hematogenous dissemination of medulloblastoma offers a new opportunity to diagnose and treat lethal disseminated medulloblastoma.


Asunto(s)
Meduloblastoma/irrigación sanguínea , Meduloblastoma/patología , Neoplasias Meníngeas/irrigación sanguínea , Neoplasias Meníngeas/secundario , Aloinjertos , Animales , Línea Celular Tumoral , Quimiocina CCL2/metabolismo , Cromosomas Humanos Par 10/genética , Femenino , Humanos , Masculino , Meduloblastoma/genética , Ratones SCID , Células Neoplásicas Circulantes , Parabiosis
2.
Mol Cell ; 84(2): 261-276.e18, 2024 Jan 18.
Artículo en Inglés | MEDLINE | ID: mdl-38176414

RESUMEN

A hallmark of high-risk childhood medulloblastoma is the dysregulation of RNA translation. Currently, it is unknown whether medulloblastoma dysregulates the translation of putatively oncogenic non-canonical open reading frames (ORFs). To address this question, we performed ribosome profiling of 32 medulloblastoma tissues and cell lines and observed widespread non-canonical ORF translation. We then developed a stepwise approach using multiple CRISPR-Cas9 screens to elucidate non-canonical ORFs and putative microproteins implicated in medulloblastoma cell survival. We determined that multiple lncRNA-ORFs and upstream ORFs (uORFs) exhibited selective functionality independent of main coding sequences. A microprotein encoded by one of these ORFs, ASNSD1-uORF or ASDURF, was upregulated, associated with MYC-family oncogenes, and promoted medulloblastoma cell survival through engagement with the prefoldin-like chaperone complex. Our findings underscore the fundamental importance of non-canonical ORF translation in medulloblastoma and provide a rationale to include these ORFs in future studies seeking to define new cancer targets.


Asunto(s)
Neoplasias Cerebelosas , Meduloblastoma , Humanos , Biosíntesis de Proteínas , Meduloblastoma/genética , Sistemas de Lectura Abierta/genética , Supervivencia Celular/genética , Neoplasias Cerebelosas/genética
3.
Mol Cell ; 84(2): 188-190, 2024 Jan 18.
Artículo en Inglés | MEDLINE | ID: mdl-38242097

RESUMEN

In this issue of Molecular Cell, Hofman et al.1 identify the translation of a non-canonical upstream open reading frame of the ASNSD1 gene into a microprotein that supports medulloblastoma growth.


Asunto(s)
Neoplasias Cerebelosas , Meduloblastoma , Humanos , Meduloblastoma/genética , Sistemas de Lectura Abierta , Micropéptidos , Carcinogénesis/genética , Transformación Celular Neoplásica/genética , Neoplasias Cerebelosas/genética , Biosíntesis de Proteínas
4.
Genes Dev ; 36(11-12): 650-651, 2022 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-35835507

RESUMEN

Here I discuss the study in this issue of Genes & Development by Youn et al. (pp. 737-751), which describes defined and diverse roles of primary cilia in molecularly distinct medulloblastoma subgroups, highlighting once again the importance of designing subgroup-specific therapeutic approaches for this tumor.


Asunto(s)
Neoplasias Cerebelosas , Meduloblastoma , Neoplasias Cerebelosas/genética , Cilios/genética , Humanos , Meduloblastoma/genética
5.
Genes Dev ; 36(11-12): 737-751, 2022 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-35798383

RESUMEN

The primary cilium, a signaling organelle projecting from the surface of a cell, controls cellular physiology and behavior. The presence or absence of primary cilia is a distinctive feature of a given tumor type; however, whether and how the primary cilium contributes to tumorigenesis are unknown for most tumors. Medulloblastoma (MB) is a common pediatric brain cancer comprising four groups: SHH, WNT, group 3 (G3), and group 4 (G4). From 111 cases of MB, we show that primary cilia are abundant in SHH and WNT MBs but rare in G3 and G4 MBs. Using WNT and G3 MB mouse models, we show that primary cilia promote WNT MB by facilitating translation of mRNA encoding ß-catenin, a major oncoprotein driving WNT MB, whereas cilium loss promotes G3 MB by disrupting cell cycle control and destabilizing the genome. Our findings reveal tumor type-specific ciliary functions and underlying molecular mechanisms. Moreover, we expand the function of primary cilia to translation control and reveal a molecular mechanism by which cilia regulate cell cycle progression, thereby providing new frameworks for studying cilium function in normal and pathologic conditions.


Asunto(s)
Neoplasias Encefálicas , Neoplasias Cerebelosas , Meduloblastoma , Animales , Neoplasias Encefálicas/patología , Ciclo Celular/genética , Neoplasias Cerebelosas/genética , Cilios/genética , Humanos , Meduloblastoma/genética , Ratones
6.
Cell ; 155(3): 567-81, 2013 Oct 24.
Artículo en Inglés | MEDLINE | ID: mdl-24139898

RESUMEN

Mutation is a fundamental process in tumorigenesis. However, the degree to which the rate of somatic mutation varies across the human genome and the mechanistic basis underlying this variation remain to be fully elucidated. Here, we performed a cross-cancer comparison of 402 whole genomes comprising a diverse set of childhood and adult tumors, including both solid and hematopoietic malignancies. Surprisingly, we found that the inactive X chromosome of many female cancer genomes accumulates on average twice and up to four times as many somatic mutations per megabase, as compared to the individual autosomes. Whole-genome sequencing of clonally expanded hematopoietic stem/progenitor cells (HSPCs) from healthy individuals and a premalignant myelodysplastic syndrome (MDS) sample revealed no X chromosome hypermutation. Our data suggest that hypermutation of the inactive X chromosome is an early and frequent feature of tumorigenesis resulting from DNA replication stress in aberrantly proliferating cells.


Asunto(s)
Cromosomas Humanos X , Mutación , Neoplasias/genética , Inactivación del Cromosoma X , Adulto , Anciano , Replicación del ADN , Femenino , Humanos , Masculino , Meduloblastoma/genética , Meduloblastoma/patología , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/patología , Polimorfismo de Nucleótido Simple , Fase S
7.
Nature ; 609(7929): 1021-1028, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-36131014

RESUMEN

Medulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong links to early development of the hindbrain1-4. Mutations that activate Sonic hedgehog signalling lead to Sonic hedgehog MB in the upper rhombic lip (RL) granule cell lineage5-8. By contrast, mutations that activate WNT signalling lead to WNT MB in the lower RL9,10. However, little is known about the more commonly occurring group 4 (G4) MB, which is thought to arise in the unipolar brush cell lineage3,4. Here we demonstrate that somatic mutations that cause G4 MB converge on the core binding factor alpha (CBFA) complex and mutually exclusive alterations that affect CBFA2T2, CBFA2T3, PRDM6, UTX and OTX2. CBFA2T2 is expressed early in the progenitor cells of the cerebellar RL subventricular zone in Homo sapiens, and G4 MB transcriptionally resembles these progenitors but are stalled in developmental time. Knockdown of OTX2 in model systems relieves this differentiation blockade, which allows MB cells to spontaneously proceed along normal developmental differentiation trajectories. The specific nature of the split human RL, which is destined to generate most of the neurons in the human brain, and its high level of susceptible EOMES+KI67+ unipolar brush cell progenitor cells probably predisposes our species to the development of G4 MB.


Asunto(s)
Diferenciación Celular , Neoplasias Cerebelosas , Meduloblastoma , Metencéfalo , Diferenciación Celular/genética , Linaje de la Célula , Neoplasias Cerebelosas/clasificación , Neoplasias Cerebelosas/genética , Neoplasias Cerebelosas/patología , Cerebelo/embriología , Cerebelo/patología , Subunidades alfa del Factor de Unión al Sitio Principal/genética , Proteínas Hedgehog/metabolismo , Histona Demetilasas , Humanos , Antígeno Ki-67/metabolismo , Meduloblastoma/clasificación , Meduloblastoma/genética , Meduloblastoma/patología , Metencéfalo/embriología , Metencéfalo/patología , Proteínas Musculares , Mutación , Factores de Transcripción Otx/deficiencia , Factores de Transcripción Otx/genética , Proteínas Represoras , Proteínas de Dominio T Box/metabolismo , Factores de Transcripción
8.
Genes Dev ; 34(17-18): 1161-1176, 2020 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-32820036

RESUMEN

Medulloblastoma is a malignant childhood brain tumor arising from the developing cerebellum. In Sonic Hedgehog (SHH) subgroup medulloblastoma, aberrant activation of SHH signaling causes increased proliferation of granule neuron progenitors (GNPs), and predisposes these cells to tumorigenesis. A second, cooperating genetic hit is often required to push these hyperplastic cells to malignancy and confer mutation-specific characteristics associated with oncogenic signaling. Somatic loss-of-function mutations of the transcriptional corepressor BCOR are recurrent and enriched in SHH medulloblastoma. To investigate BCOR as a putative tumor suppressor, we used a genetically engineered mouse model to delete exons 9/10 of Bcor (BcorΔE9-10 ) in GNPs during development. This mutation leads to reduced expression of C-terminally truncated BCOR (BCORΔE9-10). While BcorΔE9-10 alone did not promote tumorigenesis or affect GNP differentiation, BcorΔE9-10 combined with loss of the SHH receptor gene Ptch1 resulted in fully penetrant medulloblastomas. In Ptch1+/- ;BcorΔE9-10 tumors, the growth factor gene Igf2 was aberrantly up-regulated, and ectopic Igf2 overexpression was sufficient to drive tumorigenesis in Ptch1+/- GNPs. BCOR directly regulates Igf2, likely through the PRC1.1 complex; the repressive histone mark H2AK119Ub is decreased at the Igf2 promoter in Ptch1+/- ;BcorΔE9-10 tumors. Overall, our data suggests that BCOR-PRC1.1 disruption leads to Igf2 overexpression, which transforms preneoplastic cells to malignant tumors.


Asunto(s)
Neoplasias Cerebelosas/genética , Regulación Neoplásica de la Expresión Génica/genética , Proteínas Hedgehog/metabolismo , Meduloblastoma/genética , Proteínas del Grupo Polycomb/metabolismo , Proteínas Represoras/genética , Animales , Carcinogénesis/genética , Modelos Animales de Enfermedad , Proteínas Hedgehog/genética , Humanos , Ratones , Mutación , Receptor Patched-1/genética , Proteínas del Grupo Polycomb/genética , Proteínas Represoras/metabolismo , Eliminación de Secuencia
9.
Cell ; 148(1-2): 59-71, 2012 Jan 20.
Artículo en Inglés | MEDLINE | ID: mdl-22265402

RESUMEN

Genomic rearrangements are thought to occur progressively during tumor development. Recent findings, however, suggest an alternative mechanism, involving massive chromosome rearrangements in a one-step catastrophic event termed chromothripsis. We report the whole-genome sequencing-based analysis of a Sonic-Hedgehog medulloblastoma (SHH-MB) brain tumor from a patient with a germline TP53 mutation (Li-Fraumeni syndrome), uncovering massive, complex chromosome rearrangements. Integrating TP53 status with microarray and deep sequencing-based DNA rearrangement data in additional patients reveals a striking association between TP53 mutation and chromothripsis in SHH-MBs. Analysis of additional tumor entities substantiates a link between TP53 mutation and chromothripsis, and indicates a context-specific role for p53 in catastrophic DNA rearrangements. Among these, we observed a strong association between somatic TP53 mutations and chromothripsis in acute myeloid leukemia. These findings connect p53 status and chromothripsis in specific tumor types, providing a genetic basis for understanding particularly aggressive subtypes of cancer.


Asunto(s)
Neoplasias Encefálicas/genética , Reordenamiento Génico , Meduloblastoma/genética , Proteína p53 Supresora de Tumor/genética , Animales , Niño , Aberraciones Cromosómicas , Variaciones en el Número de Copia de ADN , Análisis Mutacional de ADN , Modelos Animales de Enfermedad , Humanos , Leucemia Mieloide Aguda/genética , Síndrome de Li-Fraumeni/fisiopatología , Ratones , Persona de Mediana Edad
10.
Annu Rev Neurosci ; 41: 207-232, 2018 07 08.
Artículo en Inglés | MEDLINE | ID: mdl-29641939

RESUMEN

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.


Asunto(s)
Neoplasias Cerebelosas , Meduloblastoma , Terapia Molecular Dirigida/métodos , Animales , Neoplasias Cerebelosas/clasificación , Neoplasias Cerebelosas/genética , Neoplasias Cerebelosas/terapia , Humanos , Meduloblastoma/clasificación , Meduloblastoma/genética , Meduloblastoma/terapia
11.
Nature ; 580(7803): 396-401, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32296180

RESUMEN

Cancer genomics has revealed many genes and core molecular processes that contribute to human malignancies, but the genetic and molecular bases of many rare cancers remains unclear. Genetic predisposition accounts for 5 to 10% of cancer diagnoses in children1,2, and genetic events that cooperate with known somatic driver events are poorly understood. Pathogenic germline variants in established cancer predisposition genes have been recently identified in 5% of patients with the malignant brain tumour medulloblastoma3. Here, by analysing all protein-coding genes, we identify and replicate rare germline loss-of-function variants across ELP1 in 14% of paediatric patients with the medulloblastoma subgroup Sonic Hedgehog (MBSHH). ELP1 was the most common medulloblastoma predisposition gene and increased the prevalence of genetic predisposition to 40% among paediatric patients with MBSHH. Parent-offspring and pedigree analyses identified two families with a history of paediatric medulloblastoma. ELP1-associated medulloblastomas were restricted to the molecular SHHα subtype4 and characterized by universal biallelic inactivation of ELP1 owing to somatic loss of chromosome arm 9q. Most ELP1-associated medulloblastomas also exhibited somatic alterations in PTCH1, which suggests that germline ELP1 loss-of-function variants predispose individuals to tumour development in combination with constitutive activation of SHH signalling. ELP1 is the largest subunit of the evolutionarily conserved Elongator complex, which catalyses translational elongation through tRNA modifications at the wobble (U34) position5,6. Tumours from patients with ELP1-associated MBSHH were characterized by a destabilized Elongator complex, loss of Elongator-dependent tRNA modifications, codon-dependent translational reprogramming, and induction of the unfolded protein response, consistent with loss of protein homeostasis due to Elongator deficiency in model systems7-9. Thus, genetic predisposition to proteome instability may be a determinant in the pathogenesis of paediatric brain cancers. These results support investigation of the role of protein homeostasis in other cancer types and potential for therapeutic interference.


Asunto(s)
Neoplasias Cerebelosas/metabolismo , Mutación de Línea Germinal , Meduloblastoma/metabolismo , Factores de Elongación Transcripcional/metabolismo , Neoplasias Cerebelosas/genética , Neoplasias Cerebelosas/patología , Niño , Femenino , Humanos , Masculino , Meduloblastoma/genética , Linaje , ARN de Transferencia/metabolismo , Factores de Elongación Transcripcional/genética
12.
Mol Cell ; 70(5): 825-841.e6, 2018 06 07.
Artículo en Inglés | MEDLINE | ID: mdl-29861161

RESUMEN

Super-enhancers are large clusters of enhancers that activate gene expression. Broad trimethyl histone H3 lysine 4 (H3K4me3) often defines active tumor suppressor genes. However, how these epigenomic signatures are regulated for tumor suppression is little understood. Here we show that brain-specific knockout of the H3K4 methyltransferase MLL4 (a COMPASS-like enzyme, also known as KMT2D) in mice spontaneously induces medulloblastoma. Mll4 loss upregulates oncogenic Ras and Notch pathways while downregulating neuronal gene expression programs. MLL4 enhances DNMT3A-catalyzed DNA methylation and SIRT1/BCL6-mediated H4K16 deacetylation, which antagonize expression of Ras activators and Notch pathway components, respectively. Notably, Mll4 loss downregulates tumor suppressor genes (e.g., Dnmt3a and Bcl6) by diminishing broad H3K4me3 and super-enhancers and also causes widespread impairment of these epigenomic signatures during medulloblastoma genesis. These findings suggest an anti-tumor role for super-enhancers and provide a unique tumor-suppressive mechanism in which MLL4 is necessary to maintain broad H3K4me3 and super-enhancers at tumor suppressor genes.


Asunto(s)
Neoplasias Cerebelosas/genética , Metilación de ADN , Genes Supresores de Tumor , N-Metiltransferasa de Histona-Lisina/genética , Meduloblastoma/genética , Oncogenes , Procesamiento Proteico-Postraduccional , Acetilación , Animales , Proliferación Celular , Neoplasias Cerebelosas/metabolismo , Neoplasias Cerebelosas/patología , ADN (Citosina-5-)-Metiltransferasas/genética , ADN (Citosina-5-)-Metiltransferasas/metabolismo , ADN Metiltransferasa 3A , Regulación Neoplásica de la Expresión Génica , Genes ras , N-Metiltransferasa de Histona-Lisina/deficiencia , Lisina , Meduloblastoma/metabolismo , Meduloblastoma/patología , Ratones Noqueados , Proteínas Proto-Oncogénicas c-bcl-6/genética , Proteínas Proto-Oncogénicas c-bcl-6/metabolismo , Receptores Notch/genética , Receptores Notch/metabolismo , Transducción de Señal , Sirtuina 1/genética , Sirtuina 1/metabolismo
13.
Am J Pathol ; 194(11): 2007-2022, 2024 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-39168365

RESUMEN

Germline mutations of homologous-recombination (HR) genes are among the top contributors to medulloblastomas. A significant portion of human medulloblastomas exhibit genomic signatures of HR defects. Whether ablation of Brca2 and Palb2, and their related Brca1 and Bccip genes, in the mouse brain can differentially initiate medulloblastomas was explored here. Conditional knockout mouse models of these HR genes and a conditional knockdown of Bccip (shBccip-KD) were established. Deletion of any of these genes led to microcephaly and neurologic defects, with Brca1- and Bccip- producing the worst defects. Trp53 co-deletion significantly rescued the microcephaly with Brca1, Palb2, and Brca2 deficiency but exhibited limited impact on Bccip- mice. For the first time, inactivation of either Brca1 or Palb2 with Trp53 was found to induce medulloblastomas. Despite shBccip-CKD being highly penetrative, Bccip/Trp53 deletions failed to induce medulloblastomas. The tumors displayed diverse immunohistochemical features and chromosome copy number variation. Although there were widespread up-regulations of cell proliferative pathways, most of the tumors expressed biomarkers of the sonic hedgehog subgroup. The medulloblastomas developed from Brca1-, Palb2-, and Brca2- mice were highly sensitive to a poly (ADP-ribose) polymerase inhibitor but not the ones from shBccip-CKD mice. These models recapitulate the spontaneous medulloblastoma development with high penetrance and a narrow time window, providing ideal platforms to test therapeutic agents with the ability to differentiate HR-defective and HR-proficient tumors.


Asunto(s)
Proteína BRCA1 , Proteína BRCA2 , Neoplasias Cerebelosas , Recombinación Homóloga , Meduloblastoma , Ratones Noqueados , Proteína p53 Supresora de Tumor , Animales , Meduloblastoma/genética , Meduloblastoma/patología , Meduloblastoma/metabolismo , Ratones , Neoplasias Cerebelosas/genética , Neoplasias Cerebelosas/patología , Recombinación Homóloga/genética , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Proteína BRCA1/genética , Proteína BRCA1/metabolismo , Proteína BRCA2/genética , Proteína BRCA2/metabolismo , Proteína del Grupo de Complementación N de la Anemia de Fanconi/genética , Proteína del Grupo de Complementación N de la Anemia de Fanconi/metabolismo
14.
J Pathol ; 262(4): 427-440, 2024 04.
Artículo en Inglés | MEDLINE | ID: mdl-38229567

RESUMEN

Radiotherapy is one of the standard therapeutic regimens for medulloblastoma (MB). Tumor cells utilize DNA damage repair (DDR) mechanisms to survive and develop resistance during radiotherapy. It has been found that targeting DDR sensitizes tumor cells to radiotherapy in several types of cancer, but whether and how DDR pathways are involved in the MB radiotherapy response remain to be determined. Single-cell RNA sequencing was carried out on 38 MB tissues, followed by expression enrichment assays. Fanconi anemia group D2 gene (FANCD2) expression was evaluated in MB samples and public MB databases. The function of FANCD2 in MB cells was examined using cell counting assays (CCK-8), clone formation, lactate dehydrogenase activity, and in mouse orthotopic models. The FANCD2-related signaling pathway was investigated using assays of peroxidation, a malondialdehyde assay, a reduced glutathione assay, and using FerroOrange to assess intracellular iron ions (Fe2+ ). Here, we report that FANCD2 was highly expressed in the malignant sonic hedgehog (SHH) MB subtype (SHH-MB). FANCD2 played an oncogenic role and predicted worse prognosis in SHH-MB patients. Moreover, FANCD2 knockdown markedly suppressed viability, mobility, and growth of SHH-MB cells and sensitized SHH-MB cells to irradiation. Mechanistically, FANCD2 deficiency led to an accumulation of Fe2+ due to increased divalent metal transporter 1 expression and impaired glutathione peroxidase 4 activity, which further activated ferroptosis and reduced proliferation of SHH-MB cells. Using an orthotopic mouse model, we observed that radiotherapy combined with silencing FANCD2 significantly inhibited the growth of SHH-MB cell-derived tumors in vivo. Our study revealed FANCD2 as a potential therapeutic target in SHH-MB and silencing FANCD2 could sensitize SHH-MB cells to radiotherapy via inducing ferroptosis. © 2024 The Pathological Society of Great Britain and Ireland.


Asunto(s)
Neoplasias Cerebelosas , Anemia de Fanconi , Ferroptosis , Meduloblastoma , Ratones , Animales , Humanos , Meduloblastoma/genética , Meduloblastoma/radioterapia , Ferroptosis/genética , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Neoplasias Cerebelosas/genética , Neoplasias Cerebelosas/radioterapia , Línea Celular Tumoral , Proteína del Grupo de Complementación D2 de la Anemia de Fanconi/genética
15.
Nature ; 574(7780): 707-711, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31664194

RESUMEN

In cancer, recurrent somatic single-nucleotide variants-which are rare in most paediatric cancers-are confined largely to protein-coding genes1-3. Here we report highly recurrent hotspot mutations (r.3A>G) of U1 spliceosomal small nuclear RNAs (snRNAs) in about 50% of Sonic hedgehog (SHH) medulloblastomas. These mutations were not present across other subgroups of medulloblastoma, and we identified these hotspot mutations in U1 snRNA in only <0.1% of 2,442 cancers, across 36 other tumour types. The mutations occur in 97% of adults (subtype SHHδ) and 25% of adolescents (subtype SHHα) with SHH medulloblastoma, but are largely absent from SHH medulloblastoma in infants. The U1 snRNA mutations occur in the 5' splice-site binding region, and snRNA-mutant tumours have significantly disrupted RNA splicing and an excess of 5' cryptic splicing events. Alternative splicing mediated by mutant U1 snRNA inactivates tumour-suppressor genes (PTCH1) and activates oncogenes (GLI2 and CCND2), and represents a target for therapy. These U1 snRNA mutations provide an example of highly recurrent and tissue-specific mutations of a non-protein-coding gene in cancer.


Asunto(s)
Neoplasias Cerebelosas/genética , Proteínas Hedgehog/genética , Meduloblastoma/genética , ARN Nuclear Pequeño/genética , Adolescente , Adulto , Empalme Alternativo , Proteínas Hedgehog/metabolismo , Humanos , Mutación , Sitios de Empalme de ARN , Empalme del ARN
16.
Nature ; 572(7767): 74-79, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31341285

RESUMEN

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.


Asunto(s)
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/patología
17.
Nature ; 572(7767): 67-73, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31043743

RESUMEN

Study of the origin and development of cerebellar tumours has been hampered by the complexity and heterogeneity of cerebellar cells that change over the course of development. Here we use single-cell transcriptomics to study more than 60,000 cells from the developing mouse cerebellum and show that different molecular subgroups of childhood cerebellar tumours mirror the transcription of cells from distinct, temporally restricted cerebellar lineages. The Sonic Hedgehog medulloblastoma subgroup transcriptionally mirrors the granule cell hierarchy as expected, while group 3 medulloblastoma resembles Nestin+ stem cells, group 4 medulloblastoma resembles unipolar brush cells, and PFA/PFB ependymoma and cerebellar pilocytic astrocytoma resemble the prenatal gliogenic progenitor cells. Furthermore, single-cell transcriptomics of human childhood cerebellar tumours demonstrates that many bulk tumours contain a mixed population of cells with divergent differentiation. Our data highlight cerebellar tumours as a disorder of early brain development and provide a proximate explanation for the peak incidence of cerebellar tumours in early childhood.


Asunto(s)
Neoplasias Cerebelosas/genética , Neoplasias Cerebelosas/patología , Evolución Molecular , Feto/metabolismo , Regulación del Desarrollo de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Transcripción Genética , Animales , Neoplasias Cerebelosas/clasificación , Cerebelo/citología , Cerebelo/embriología , Cerebelo/metabolismo , Niño , Femenino , Feto/citología , Glioma/clasificación , Glioma/genética , Glioma/patología , Humanos , Meduloblastoma/clasificación , Meduloblastoma/genética , Meduloblastoma/patología , Ratones , Análisis de Secuencia de ARN , Análisis de la Célula Individual , Factores de Tiempo , Transcriptoma/genética
18.
Proc Natl Acad Sci U S A ; 119(34): e2202821119, 2022 08 23.
Artículo en Inglés | MEDLINE | ID: mdl-35969743

RESUMEN

Sonic hedgehog (Shh) signaling plays a critical role in regulating cerebellum development by maintaining the physiological proliferation of granule neuron precursors (GNPs), and its dysregulation leads to the oncogenesis of medulloblastoma. O-GlcNAcylation (O-GlcNAc) of proteins is an emerging regulator of brain function that maintains normal development and neuronal circuitry. Here, we demonstrate that O-GlcNAc transferase (OGT) in GNPs mediate the cerebellum development, and the progression of the Shh subgroup of medulloblastoma. Specifically, OGT regulates the neurogenesis of GNPs by activating the Shh signaling pathway via O-GlcNAcylation at S355 of GLI family zinc finger 2 (Gli2), which in turn promotes its deacetylation and transcriptional activity via dissociation from p300, a histone acetyltransferases. Inhibition of OGT via genetic ablation or chemical inhibition improves survival in a medulloblastoma mouse model. These data uncover a critical role for O-GlcNAc signaling in cerebellar development, and pinpoint a potential therapeutic target for Shh-associated medulloblastoma.


Asunto(s)
Neoplasias Cerebelosas , Meduloblastoma , Animales , Carcinogénesis/genética , Carcinogénesis/metabolismo , Proliferación Celular , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Neoplasias Cerebelosas/genética , Neoplasias Cerebelosas/metabolismo , Cerebelo/metabolismo , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Meduloblastoma/genética , Meduloblastoma/metabolismo , Ratones , Neurogénesis/fisiología
19.
Proc Natl Acad Sci U S A ; 119(37): e2203738119, 2022 09 13.
Artículo en Inglés | MEDLINE | ID: mdl-36067288

RESUMEN

Long noncoding RNAs (lncRNAs) play essential roles in the development and progression of many cancers. However, the contributions of lncRNAs to medulloblastoma (MB) remain poorly understood. Here, we identify Miat as an lncRNA enriched in the sonic hedgehog group of MB that is required for maintenance of a treatment-resistant stem-like phenotype in the disease. Loss of Miat results in the differentiation of tumor-initiating, stem-like MB cells and enforces the differentiation of tumorigenic stem-like MB cells into a nontumorigenic state. Miat expression in stem-like MB cells also facilitates treatment resistance by down-regulating p53 signaling and impairing radiation-induced cell death, which can be reversed by therapeutic inhibition of Miat using antisense oligonucleotides. Mechanistically, the RNA binding protein Metadherin (Mtdh), previously linked to resistance to cytotoxic therapy in cancer, binds to Miat in stem-like MB cells. Like the loss of Miat, the loss of Mtdh reduces tumorigenicity and increases sensitivity to radiation-induced death in stem-like MB cells. Moreover, Miat and Mtdh function to regulate the biogenesis of several microRNAs and facilitate tumorigenesis and treatment resistance. Taken together, these data reveal an essential role for the lncRNA Miat in sustaining a treatment-resistant pool of tumorigenic stem-like MB cells.


Asunto(s)
Carcinogénesis , Neoplasias Cerebelosas , Meduloblastoma , Proteínas de la Membrana , MicroARNs , ARN Largo no Codificante , Proteínas de Unión al ARN , Carcinogénesis/genética , Carcinogénesis/metabolismo , Neoplasias Cerebelosas/genética , Neoplasias Cerebelosas/patología , Humanos , Meduloblastoma/genética , Meduloblastoma/patología , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , ARN Largo no Codificante/metabolismo , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo
20.
Genes Chromosomes Cancer ; 63(4): e23233, 2024 04.
Artículo en Inglés | MEDLINE | ID: mdl-38607297

RESUMEN

Medulloblastomas, the most common malignant pediatric brain tumors, can be classified into the wingless, sonic hedgehog (SHH), group 3, and group 4 subgroups. Among them, the SHH subgroup with the TP53 mutation and group 3 generally present with the worst patient outcomes due to their high rates of recurrence and metastasis. A novel and effective treatment for refractory medulloblastomas is urgently needed. To date, the tumor microenvironment (TME) has been shown to influence tumor growth, recurrence, and metastasis through immunosuppression, angiogenesis, and chronic inflammation. Treatments targeting TME components have emerged as promising approaches to the treatment of solid tumors. In this review, we summarize progress in research on medulloblastoma microenvironment components and their interactions. We also discuss challenges and future research directions for TME-targeting medulloblastoma therapy.


Asunto(s)
Neoplasias Encefálicas , Neoplasias Cerebelosas , Meduloblastoma , Humanos , Niño , Proteínas Hedgehog/genética , Meduloblastoma/genética , Microambiente Tumoral/genética , Neoplasias Cerebelosas/genética
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