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1.
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
2.
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
3.
FASEB J ; 27(4): 1330-41, 2013 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-23271049

RESUMEN

Scalloped (SD) is a transcription factor characterized by a TEA/ATTS DNA binding domain. To activate transcription, SD must interact with its coactivators, including Yorkie (YKI) or Vestigial (VG). YKI is the downstream effector of the Hippo signaling pathway that plays a key role in the control of tissue growth. The core components of this pathway are two kinases, Hippo (HPO) and Warts (WTS), which negatively regulate the activity of the SD/YKI complex, retaining YKI in the cytoplasm. We previously showed that HPO kinase can also reduce SD/VG transcriptional activity in Drosophila S2 cells. We further investigated the relationship between the SD/VG complex and the Hippo pathway. We show here that HPO overexpression suppresses overgrowth induced by SD/VG in vivo during Drosophila development. Using S2 cells, we show that HPO promotes the translocation of SD to the cytoplasm in a CRM1-dependent manner, thereby inhibiting the induction of SD/VG target genes. Using RNAi-mediated depletion of yki and a mutant SD protein unable to interact with YKI, we demonstrate that HPO regulates SD localization independently of YKI. This function requires HPO kinase activity, yet surprisingly, not its downstream effector kinase WTS. Taken together, these observations reveal a new and unexpected role of HPO kinase in the regulation of a transcription factor independently of YKI.


Asunto(s)
Citoplasma/metabolismo , Proteínas de Drosophila/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Carioferinas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , Factores de Transcripción/metabolismo , Animales , Proliferación Celular , Drosophila , Proteínas de Drosophila/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Transducción de Señal/genética , Factores de Transcripción/genética , Transcripción Genética/fisiología , Verrugas/genética , Verrugas/metabolismo , Proteína Exportina 1
4.
bioRxiv ; 2024 May 24.
Artículo en Inglés | MEDLINE | ID: mdl-38826258

RESUMEN

This article describes the Cell Maps for Artificial Intelligence (CM4AI) project and its goals, methods, standards, current datasets, software tools , status, and future directions. CM4AI is the Functional Genomics Data Generation Project in the U.S. National Institute of Health's (NIH) Bridge2AI program. Its overarching mission is to produce ethical, AI-ready datasets of cell architecture, inferred from multimodal data collected for human cell lines, to enable transformative biomedical AI research.

5.
Nat Cancer ; 5(7): 1082-1101, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38816660

RESUMEN

Dose-limiting toxicity poses a major limitation to the clinical utility of targeted cancer therapies, often arising from target engagement in nonmalignant tissues. This obstacle can be minimized by targeting cancer dependencies driven by proteins with tissue-restricted and/or tumor-restricted expression. In line with another recent report, we show here that, in acute myeloid leukemia (AML), suppression of the myeloid-restricted PIK3CG/p110γ-PIK3R5/p101 axis inhibits protein kinase B/Akt signaling and compromises AML cell fitness. Furthermore, silencing the genes encoding PIK3CG/p110γ or PIK3R5/p101 sensitizes AML cells to established AML therapies. Importantly, we find that existing small-molecule inhibitors against PIK3CG are insufficient to achieve a sustained long-term antileukemic effect. To address this concern, we developed a proteolysis-targeting chimera (PROTAC) heterobifunctional molecule that specifically degrades PIK3CG and potently suppresses AML progression alone and in combination with venetoclax in human AML cell lines, primary samples from patients with AML and syngeneic mouse models.


Asunto(s)
Fosfatidilinositol 3-Quinasa Clase Ib , Leucemia Mieloide Aguda , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/genética , Humanos , Animales , Ratones , Transducción de Señal/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasa Clase Ib/metabolismo , Fosfatidilinositol 3-Quinasa Clase Ib/genética , Línea Celular Tumoral , Ensayos Antitumor por Modelo de Xenoinjerto , Sulfonamidas/farmacología , Sulfonamidas/uso terapéutico , Proteolisis/efectos de los fármacos , Femenino , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico
6.
J Biol Chem ; 287(13): 10509-10524, 2012 Mar 23.
Artículo en Inglés | MEDLINE | ID: mdl-22315224

RESUMEN

HIC1 (hypermethylated in cancer 1) is a tumor suppressor gene epigenetically silenced or deleted in many human cancers. HIC1 is involved in regulatory loops modulating p53- and E2F1-dependent cell survival, growth control, and stress responses. HIC1 is also essential for normal development because Hic1-deficient mice die perinatally and exhibit gross developmental defects throughout the second half of development. HIC1 encodes a transcriptional repressor with five C(2)H(2) zinc fingers mediating sequence-specific DNA binding and two repression domains: an N-terminal BTB/POZ domain and a central region recruiting CtBP and NuRD complexes. By yeast two-hybrid screening, we identified the Polycomb-like protein hPCL3 as a novel co-repressor for HIC1. Using multiple biochemical strategies, we demonstrated that HIC1 interacts with hPCL3 and its paralog PHF1 to form a stable complex with the PRC2 members EZH2, EED, and Suz12. Confirming the implication of HIC1 in Polycomb recruitment, we showed that HIC1 shares some of its target genes with PRC2, including ATOH1. Depletion of HIC1 by siRNA interference leads to a partial displacement of EZH2 from the ATOH1 promoter. Furthermore, in vivo, ATOH1 repression by HIC1 is associated with Polycomb activity during mouse cerebellar development. Thus, our results identify HIC1 as the first transcription factor in mammals able to recruit PRC2 to some target promoters through its interaction with Polycomb-like proteins.


Asunto(s)
Factores de Transcripción de Tipo Kruppel/metabolismo , Proteínas Represoras/metabolismo , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Cerebelo/embriología , Cerebelo/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Proteína Potenciadora del Homólogo Zeste 2 , Femenino , N-Metiltransferasa de Histona-Lisina/genética , N-Metiltransferasa de Histona-Lisina/metabolismo , Humanos , Factores de Transcripción de Tipo Kruppel/genética , Ratones , Proteínas de Neoplasias , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Complejo Represivo Polycomb 2 , Proteínas del Grupo Polycomb , Proteínas Represoras/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Dedos de Zinc
7.
Nat Commun ; 14(1): 3543, 2023 06 19.
Artículo en Inglés | MEDLINE | ID: mdl-37336883

RESUMEN

PEAK pseudokinases are molecular scaffolds which dimerize to regulate cell migration, morphology, and proliferation, as well as cancer progression. The mechanistic role dimerization plays in PEAK scaffolding remains unclear, as there are no structures of PEAKs in complex with their interactors. Here, we report the cryo-EM structure of dimeric PEAK3 in complex with an endogenous 14-3-3 heterodimer. Our structure reveals an asymmetric binding mode between PEAK3 and 14-3-3 stabilized by one pseudokinase domain and the SHED domain of the PEAK3 dimer. The binding interface contains a canonical phosphosite-dependent primary interaction and a unique secondary interaction not observed in previous structures of 14-3-3/client complexes. Additionally, we show that PKD regulates PEAK3/14-3-3 binding, which when prevented leads to PEAK3 nuclear enrichment and distinct protein-protein interactions. Altogether, our data demonstrate that PEAK3 dimerization forms an unusual secondary interface for 14-3-3 binding, facilitating 14-3-3 regulation of PEAK3 localization and interactome diversity.


Asunto(s)
Proteínas 14-3-3 , Proteínas del Citoesqueleto , Proteínas del Citoesqueleto/química , Proteínas 14-3-3/química , Multimerización de Proteína
8.
Nat Cancer ; 3(7): 837-851, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35668193

RESUMEN

Selinexor is a first-in-class inhibitor of the nuclear exportin XPO1 that was recently approved by the US Food and Drug Administration for the treatment of multiple myeloma and diffuse large B-cell lymphoma. In relapsed/refractory acute myeloid leukemia (AML), selinexor has shown promising activity, suggesting that selinexor-based combination therapies may have clinical potential. Here, motivated by the hypothesis that selinexor's nuclear sequestration of diverse substrates imposes pleiotropic fitness effects on AML cells, we systematically catalog the pro- and anti-fitness consequences of selinexor treatment. We discover that selinexor activates PI3Kγ-dependent AKT signaling in AML by upregulating the purinergic receptor P2RY2. Inhibiting this axis potentiates the anti-leukemic effects of selinexor in AML cell lines, patient-derived primary cultures and multiple mouse models of AML. In a syngeneic, MLL-AF9-driven mouse model of AML, treatment with selinexor and ipatasertib outperforms both standard-of-care chemotherapy and chemotherapy with selinexor. Together, these findings establish drug-induced P2RY2-AKT signaling as an actionable consequence of XPO1 inhibition in AML.


Asunto(s)
Leucemia Mieloide Aguda , Proteínas Proto-Oncogénicas c-akt , Animales , Protocolos de Quimioterapia Combinada Antineoplásica , Carioferinas/antagonistas & inhibidores , Leucemia Mieloide Aguda/tratamiento farmacológico , Ratones , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptores Citoplasmáticos y Nucleares/antagonistas & inhibidores , Receptores Citoplasmáticos y Nucleares/metabolismo , Receptores Purinérgicos P2Y2/metabolismo , Estados Unidos , Proteína Exportina 1
9.
Leukemia ; 36(6): 1585-1595, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35474100

RESUMEN

By querying metabolic pathways associated with leukemic stemness and survival in multiple AML datasets, we nominated SLC7A11 encoding the xCT cystine importer as a putative AML dependency. Genetic and chemical inhibition of SLC7A11 impaired the viability and clonogenic capacity of AML cell lines in a cysteine-dependent manner. Sulfasalazine, a broadly available drug with xCT inhibitory activity, had anti-leukemic activity against primary AML samples in ex vivo cultures. Multiple metabolic pathways were impacted upon xCT inhibition, resulting in depletion of glutathione pools in leukemic cells and oxidative stress-dependent cell death, only in part through ferroptosis. Higher expression of cysteine metabolism genes and greater cystine dependency was noted in NPM1-mutated AMLs. Among eight anti-leukemic drugs, the anthracycline daunorubicin was identified as the top synergistic agent in combination with sulfasalazine in vitro. Addition of sulfasalazine at a clinically relevant concentration significantly augmented the anti-leukemic activity of a daunorubicin-cytarabine combination in a panel of 45 primary samples enriched in NPM1-mutated AML. These results were confirmed in vivo in a patient-derived xenograft model. Collectively, our results nominate cystine import as a druggable target in AML and raise the possibility to repurpose sulfasalazine for the treatment of AML, notably in combination with chemotherapy.


Asunto(s)
Cistina , Leucemia Mieloide Aguda , Línea Celular Tumoral , Cisteína , Cistina/metabolismo , Cistina/uso terapéutico , Daunorrubicina/farmacología , Daunorrubicina/uso terapéutico , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Proteínas Nucleares , Sulfasalazina/farmacología , Sulfasalazina/uso terapéutico
10.
Nat Commun ; 13(1): 4061, 2022 07 13.
Artículo en Inglés | MEDLINE | ID: mdl-35831316

RESUMEN

Most lncRNAs display species-specific expression patterns suggesting that animal models of cancer may only incompletely recapitulate the regulatory crosstalk between lncRNAs and oncogenic pathways in humans. Among these pathways, Sonic Hedgehog (SHH) signaling is aberrantly activated in several human cancer entities. We unravel that aberrant expression of the primate-specific lncRNA HedgeHog Interacting Protein-AntiSense 1 (HHIP-AS1) is a hallmark of SHH-driven tumors including medulloblastoma and atypical teratoid/rhabdoid tumors. HHIP-AS1 is actively transcribed from a bidirectional promoter shared with SHH regulator HHIP. Knockdown of HHIP-AS1 induces mitotic spindle deregulation impairing tumorigenicity in vitro and in vivo. Mechanistically, HHIP-AS1 binds directly to the mRNA of cytoplasmic dynein 1 intermediate chain 2 (DYNC1I2) and attenuates its degradation by hsa-miR-425-5p. We uncover that neither HHIP-AS1 nor the corresponding regulatory element in DYNC1I2 are evolutionary conserved in mice. Taken together, we discover an lncRNA-mediated mechanism that enables the pro-mitotic effects of SHH pathway activation in human tumors.


Asunto(s)
Neoplasias Cerebelosas , Meduloblastoma , MicroARNs , ARN Largo no Codificante , Animales , Proteínas Portadoras/metabolismo , Línea Celular Tumoral , Proliferación Celular , Neoplasias Cerebelosas/genética , Dineínas/metabolismo , Regulación Neoplásica de la Expresión Génica , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Humanos , Meduloblastoma/genética , Glicoproteínas de Membrana/metabolismo , Ratones , MicroARNs/genética , ARN Largo no Codificante/genética
11.
mSystems ; 6(5): e0038821, 2021 Oct 26.
Artículo en Inglés | MEDLINE | ID: mdl-34519533

RESUMEN

Current epidemics, such as AIDS or flu, and the emergence of new threatening pathogens, such as the one causing the current coronavirus disease 2019 (COVID-19) pandemic, represent major global health challenges. While vaccination is an important part of the arsenal to counter the spread of viral diseases, it presents limitations and needs to be complemented by efficient therapeutic solutions. Intricate knowledge of host-pathogen interactions is a powerful tool to identify host-dependent vulnerabilities that can be exploited to dampen viral replication. Such host-directed antiviral therapies are promising and are less prone to the development of drug-resistant viral strains. Here, we first describe proteomics-based strategies that allow the rapid characterization of host-pathogen interactions. We then discuss how such data can be exploited to help prioritize compounds with potential host-directed antiviral activity that can be tested in preclinical models.

12.
Cell Rep ; 34(13): 108904, 2021 03 30.
Artículo en Inglés | MEDLINE | ID: mdl-33789110

RESUMEN

GABAergic interneurons migrate long distances through stereotyped migration programs toward specific laminar positions. During their migration, GABAergic interneurons are morphologically alike but then differentiate into a rich array of interneuron subtypes critical for brain function. How interneuron subtypes acquire their final phenotypic traits remains largely unknown. Here, we show that cerebellar molecular layer GABAergic interneurons, derived from the same progenitor pool, use separate migration paths to reach their laminar position and differentiate into distinct basket cell (BC) and stellate cell (SC) GABAergic interneuron subtypes. Using two-photon live imaging, we find that SC final laminar position requires an extra step of tangential migration supported by a subpopulation of glutamatergic granule cells (GCs). Conditional depletion of GCs affects SC differentiation but does not affect BCs. Our results reveal how timely feedforward control of inhibitory interneuron migration path regulates their terminal differentiation and, thus, establishment of the local inhibitory circuit assembly.


Asunto(s)
Diferenciación Celular , Gránulos Citoplasmáticos/metabolismo , Interneuronas/citología , Animales , Axones/metabolismo , Movimiento Celular , Neuronas GABAérgicas/citología , Interneuronas/metabolismo , Ratones Transgénicos
13.
Nat Genet ; 52(4): 408-417, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32203462

RESUMEN

Local adaptation directs populations towards environment-specific fitness maxima through acquisition of positively selected traits. However, rapid environmental changes can identify hidden fitness trade-offs that turn adaptation into maladaptation, resulting in evolutionary traps. Cancer, a disease that is prone to drug resistance, is in principle susceptible to such traps. We therefore performed pooled CRISPR-Cas9 knockout screens in acute myeloid leukemia (AML) cells treated with various chemotherapies to map the drug-dependent genetic basis of fitness trade-offs, a concept known as antagonistic pleiotropy (AP). We identified a PRC2-NSD2/3-mediated MYC regulatory axis as a drug-induced AP pathway whose ability to confer resistance to bromodomain inhibition and sensitivity to BCL-2 inhibition templates an evolutionary trap. Across diverse AML cell-line and patient-derived xenograft models, we find that acquisition of resistance to bromodomain inhibition through this pathway exposes coincident hypersensitivity to BCL-2 inhibition. Thus, drug-induced AP can be leveraged to design evolutionary traps that selectively target drug resistance in cancer.


Asunto(s)
Resistencia a Antineoplásicos/genética , Pleiotropía Genética/genética , Neoplasias/genética , Adaptación Fisiológica/genética , Animales , Evolución Biológica , Sistemas CRISPR-Cas/genética , Línea Celular , Línea Celular Tumoral , Ambiente , Aptitud Genética/genética , Células HEK293 , Células HL-60 , Humanos , Ratones , Proteínas Nucleares/genética , Fenotipo , Sitios de Carácter Cuantitativo/genética , Factores de Transcripción/genética
14.
Nat Commun ; 11(1): 3627, 2020 07 20.
Artículo en Inglés | MEDLINE | ID: mdl-32686664

RESUMEN

OTX2 is a potent oncogene that promotes tumor growth in Group 3 medulloblastoma. However, the mechanisms by which OTX2 represses neural differentiation are not well characterized. Here, we perform extensive multiomic analyses to identify an OTX2 regulatory network that controls Group 3 medulloblastoma cell fate. OTX2 silencing modulates the repressive chromatin landscape, decreases levels of PRC2 complex genes and increases the expression of neurodevelopmental transcription factors including PAX3 and PAX6. Expression of PAX3 and PAX6 is significantly lower in Group 3 medulloblastoma patients and is correlated with reduced survival, yet only PAX3 inhibits self-renewal in vitro and increases survival in vivo. Single cell RNA sequencing of Group 3 medulloblastoma tumorspheres demonstrates expression of an undifferentiated progenitor program observed in primary tumors and characterized by translation/elongation factor genes. Identification of mTORC1 signaling as a downstream effector of OTX2-PAX3 reveals roles for protein synthesis pathways in regulating Group 3 medulloblastoma pathogenesis.


Asunto(s)
Carcinogénesis/genética , Neoplasias Cerebelosas , Meduloblastoma , Factores de Transcripción Otx/metabolismo , Factor de Transcripción PAX3/genética , Animales , Carcinogénesis/metabolismo , Diferenciación Celular/genética , Línea Celular Tumoral , Proliferación Celular/genética , Neoplasias Cerebelosas/genética , Neoplasias Cerebelosas/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Meduloblastoma/genética , Meduloblastoma/metabolismo , Células Madre Neoplásicas/metabolismo , Oncogenes , Factor de Transcripción PAX3/metabolismo , Factor de Transcripción PAX6/genética , Factor de Transcripción PAX6/metabolismo , Transducción de Señal/genética
15.
Cancer Discov ; 10(12): 1894-1911, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-32826232

RESUMEN

Deciphering the impact of metabolic intervention on response to anticancer therapy may elucidate a path toward improved clinical responses. Here, we identify amino acid-related pathways connected to the folate cycle whose activation predicts sensitivity to MYC-targeting therapies in acute myeloid leukemia (AML). We establish that folate restriction and deficiency of the rate-limiting folate cycle enzyme MTHFR, which exhibits reduced-function polymorphisms in about 10% of Caucasians, induce resistance to MYC targeting by BET and CDK7 inhibitors in cell lines, primary patient samples, and syngeneic mouse models of AML. Furthermore, this effect is abrogated by supplementation with the MTHFR enzymatic product CH3-THF. Mechanistically, folate cycle disturbance reduces H3K27/K9 histone methylation and activates a SPI1 transcriptional program counteracting the effect of BET inhibition. Our data provide a rationale for screening MTHFR polymorphisms and folate cycle status to nominate patients most likely to benefit from MYC-targeting therapies. SIGNIFICANCE: Although MYC-targeting therapies represent a promising strategy for cancer treatment, evidence of predictors of sensitivity to these agents is limited. We pinpoint that folate cycle disturbance and frequent polymorphisms associated with reduced MTHFR activity promote resistance to BET inhibitors. CH3-THF supplementation thus represents a low-risk intervention to enhance their effects.See related commentary by Marando and Huntly, p. 1791.This article is highlighted in the In This Issue feature, p. 1775.


Asunto(s)
Ácido Fólico/metabolismo , Metilenotetrahidrofolato Reductasa (NADPH2)/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Animales , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas , Resistencia a Antineoplásicos , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Terapia Molecular Dirigida , Proteínas Proto-Oncogénicas c-myc/biosíntesis , Células U937
16.
EMBO Mol Med ; 11(8): e9830, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31328883

RESUMEN

Medulloblastoma (MB) is a pediatric tumor of the cerebellum divided into four groups. Group 3 is of bad prognosis and remains poorly characterized. While the current treatment involving surgery, radiotherapy, and chemotherapy often fails, no alternative therapy is yet available. Few recurrent genomic alterations that can be therapeutically targeted have been identified. Amplifications of receptors of the TGFß/Activin pathway occur at very low frequency in Group 3 MB. However, neither their functional relevance nor activation of the downstream signaling pathway has been studied. We showed that this pathway is activated in Group 3 MB with some samples showing a very strong activation. Beside genetic alterations, we demonstrated that an ActivinB autocrine stimulation is responsible for pathway activation in a subset of Group 3 MB characterized by high PMEPA1 levels. Importantly, Galunisertib, a kinase inhibitor of the cognate receptors currently tested in clinical trials for Glioblastoma patients, showed efficacy on orthotopically grafted MB-PDX. Our data demonstrate that the TGFß/Activin pathway is active in a subset of Group 3 MB and can be therapeutically targeted.


Asunto(s)
Comunicación Autocrina , Neoplasias Cerebelosas/metabolismo , Subunidades beta de Inhibinas/metabolismo , Meduloblastoma/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Factor de Crecimiento Transformador beta3/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Animales , Antineoplásicos/farmacología , Apoptosis , Línea Celular Tumoral , Proliferación Celular , Neoplasias Cerebelosas/tratamiento farmacológico , Neoplasias Cerebelosas/genética , Neoplasias Cerebelosas/patología , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Subunidades beta de Inhibinas/genética , Meduloblastoma/tratamiento farmacológico , Meduloblastoma/genética , Meduloblastoma/patología , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones Desnudos , Fosforilación , Pirazoles/farmacología , Quinolinas/farmacología , Transducción de Señal , Proteína Smad2/metabolismo , Proteína smad3/metabolismo , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta1/genética , Factor de Crecimiento Transformador beta3/genética , Carga Tumoral , Ensayos Antitumor por Modelo de Xenoinjerto
17.
Dev Cell ; 48(2): 184-199.e5, 2019 01 28.
Artículo en Inglés | MEDLINE | ID: mdl-30695697

RESUMEN

During cerebellar development, granule neuron progenitors (GNPs) proliferate by transducing Sonic Hedgehog (SHH) signaling via the primary cilium. Precise regulation of ciliogenesis, thus, ensures proper GNP pool expansion. Here, we report that Atoh1, a transcription factor required for GNPs formation, controls the presence of primary cilia, maintaining GNPs responsiveness to SHH. Loss of primary cilia abolishes the ability of Atoh1 to keep GNPs in a proliferative state. Mechanistically, Atoh1 promotes ciliogenesis by transcriptionally regulating Cep131, which facilitates centriolar satellite (CS) clustering to the basal body. Importantly, ectopic expression of Cep131 counteracts the effects of Atoh1 loss in GNPs by restoring proper localization of CS and ciliogenesis. This Atoh1-CS-primary cilium-SHH pro-proliferative pathway is also conserved in SHH-type medulloblastoma, a pediatric brain tumor arising from the GNPs. Together, our data reveal how Atoh1 modulates the primary cilium to regulate GNPs development.


Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Diferenciación Celular/fisiología , Cilios/metabolismo , Proteínas Hedgehog/metabolismo , Neuronas/metabolismo , Animales , Neoplasias Encefálicas/metabolismo , Proteínas de Ciclo Celular/metabolismo , Proliferación Celular , Neoplasias Cerebelosas/metabolismo , Meduloblastoma/metabolismo , Ratones Transgénicos , Neurogénesis
18.
Cancer Cell ; 34(3): 379-395.e7, 2018 09 10.
Artículo en Inglés | MEDLINE | ID: mdl-30205043

RESUMEN

The current consensus recognizes four main medulloblastoma subgroups (wingless, Sonic hedgehog, group 3 and group 4). While medulloblastoma subgroups have been characterized extensively at the (epi-)genomic and transcriptomic levels, the proteome and phosphoproteome landscape remain to be comprehensively elucidated. Using quantitative (phospho)-proteomics in primary human medulloblastomas, we unravel distinct posttranscriptional regulation leading to highly divergent oncogenic signaling and kinase activity profiles in groups 3 and 4 medulloblastomas. Specifically, proteomic and phosphoproteomic analyses identify aberrant ERBB4-SRC signaling in group 4. Hence, enforced expression of an activated SRC combined with p53 inactivation induces murine tumors that resemble group 4 medulloblastoma. Therefore, our integrative proteogenomics approach unveils an oncogenic pathway and potential therapeutic vulnerability in the most common medulloblastoma subgroup.


Asunto(s)
Neoplasias Cerebelosas/patología , Meduloblastoma/patología , Receptor ErbB-4/metabolismo , Familia-src Quinasas/metabolismo , Adolescente , Animales , Carcinogénesis/patología , Línea Celular Tumoral , Neoplasias Cerebelosas/genética , Cerebelo/patología , Niño , Preescolar , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Lactante , Masculino , Meduloblastoma/genética , Ratones , Ratones Transgénicos , Fosforilación , Proteoma/metabolismo , Proteómica/métodos , Transducción de Señal , Familia-src Quinasas/genética
19.
Front Biosci (Landmark Ed) ; 22(10): 1774-1791, 2017 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-28410145

RESUMEN

MicroRNAs (miRNAs) are small non-coding RNAs playing an essential role in gene expression regulation. Multiple studies have demonstrated that miRNAs are dysregulated in cancer initiation and progression, pointing out their potential as biomarkers for diagnosis, prognosis and response to treatment. With the introduction of high-throughput technologies several computational approaches have been proposed to identify cancer-associated miRNAs. Here, we present a systematic and comprehensive overview of the current knowledge concerning the computational detection of miRNAs involved in tumor onset and subtyping, with possible theranostic employment. An overview of the state of art in this field is thus proposed with the aim of supporting researchers, especially experimentalists and pathologists, in choosing the optimal approach for their case of study.


Asunto(s)
Biología Computacional/métodos , Regulación Neoplásica de la Expresión Génica , MicroARNs/genética , Neoplasias/genética , Biomarcadores de Tumor/genética , Progresión de la Enfermedad , Humanos , Neoplasias/diagnóstico , Pronóstico , ARN Mensajero/genética , Factores de Transcripción/genética
20.
Cancer Res ; 77(14): 3766-3777, 2017 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-28490517

RESUMEN

Medulloblastoma arising from the cerebellum is the most common pediatric brain malignancy, with leptomeningeal metastases often present at diagnosis and recurrence associated with poor clinical outcome. In this study, we used mouse medulloblastoma models to explore the relationship of tumor pathophysiology and dysregulated expression of the NOTCH pathway transcription factor ATOH1, which is present in aggressive medulloblastoma subtypes driven by aberrant Sonic Hedgehog/Patched (SHH/PTCH) signaling. In experiments with conditional ATOH1 mouse mutants crossed to Ptch1+/- mice, which develop SHH-driven medulloblastoma, animals with Atoh1 transgene expression developed highly penetrant medulloblastoma at a young age with extensive leptomeningeal disease and metastasis to the spinal cord and brain, resembling xenografts of human SHH medulloblastoma. Metastatic tumors retained abnormal SHH signaling like tumor xenografts. Conversely, ATOH1 expression was detected consistently in recurrent and metastatic SHH medulloblastoma. Chromatin immunoprecipitation sequencing and gene expression profiling identified candidate ATOH1 targets in tumor cells involved in development and tumorigenesis. Among these targets specific to metastatic tumors, there was an enrichment in those implicated in extracellular matrix remodeling activity, cytoskeletal network and interaction with microenvironment, indicating a shift in transcriptomic and epigenomic landscapes during metastasis. Treatment with bone morphogenetic protein or SHH pathway inhibitors decreased tumor cell proliferation and suppressed metastatic tumor growth, respectively. Our work reveals a dynamic ATOH1-driven molecular cascade underlying medulloblastoma metastasis that offers possible therapeutic opportunities. Cancer Res; 77(14); 3766-77. ©2017 AACR.


Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/biosíntesis , Neoplasias Cerebelosas/metabolismo , Meduloblastoma/metabolismo , Meduloblastoma/patología , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Proliferación Celular , Neoplasias Cerebelosas/genética , Neoplasias Cerebelosas/patología , Proteínas Hedgehog , Xenoinjertos , Humanos , Meduloblastoma/genética , Ratones , Ratones Transgénicos , Metástasis de la Neoplasia , Transducción de Señal
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