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| Open AccessTherapeutic targeting of ATR in alveolar rhabdomyosarcoma
Alveolar rhabdomyosarcoma is a clinically challenging disease due to the lack of druggable targets. Here the authors show preclinical evidence for ATR inhibitors as a therapeutic option for alveolar rhabdomyosarcoma.
- Heathcliff Dorado García
- , Fabian Pusch
- & Anton G. Henssen
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Article
| Open AccessThe HHIP-AS1 lncRNA promotes tumorigenicity through stabilization of dynein complex 1 in human SHH-driven tumors
Long non-coding RNAs (lncRNAs) can contribute to cancers that are driven by Sonic hedgehog (SHH) signaling. Here the authors report that lncRNA HHIP-AS1 stabilises the mRNA of dynein complex 1, thereby, promoting the pro-mitotic effects of SHH-driven tumors.
- Jasmin Bartl
- , Marco Zanini
- & Marc Remke
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Article
| Open AccessPro-inflammatory cytokines mediate the epithelial-to-mesenchymal-like transition of pediatric posterior fossa ependymoma
The molecular mechanisms underlying ependymoma tumorigenesis remain poorly understood. Here, single cell analysis of posterior fossa primary tumours and distal metastases highlights the role of pro-inflammatory cytokines in promoting epithelial-to-mesenchymal-transition.
- Rachael G. Aubin
- , Emma C. Troisi
- & Pablo G. Camara
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Article
| Open AccessPRMT5 activates AKT via methylation to promote tumor metastasis
‘Protein arginine methyltransferase 5 (PRMT5) is known to regulate the expression of genes involved in metastasis. Here, the authors show that PRMT5 methylates Akt and methylation is required for phosphorylation and activation of Akt; ultimately leading to the increase in expression of pro-metastatic transcription factors.
- Lei Huang
- , Xiao-Ou Zhang
- & Qiong Wu
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Article
| Open AccessClinical relevance of molecular characteristics in Burkitt lymphoma differs according to age
Survival outcomes in Burkitt lymphoma differ between adult and paediatric patients. Here, the authors show differences in mutational frequencies between age groups, and a transition between mutational profiles which occurs between 25 and 40 years.
- Birgit Burkhardt
- , Ulf Michgehl
- & Georg Lenz
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Article
| Open AccessMYCN-driven fatty acid uptake is a metabolic vulnerability in neuroblastoma
Half of high-risk neuroblastoma patients have MYCN amplification. Here, the authors show that MYCN induces fatty acid uptake and synthesis to support neuroblastoma and inhibition of a fatty acid transporter impairs tumor progression in preclinical models.
- Ling Tao
- , Mahmoud A. Mohammad
- & Eveline Barbieri
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Article
| Open AccessPoor outcome of pediatric patients with acute myeloid leukemia harboring high FLT3/ITD allelic ratios
Activating FLT3 mutations are the most common mutations in AML. Here, the authors explore the relationship between the FLT3/ITD allelic ratio and prognosis in pediatric AML patients and identify an optimal threshold to stratify patients.
- Kun-yin Qiu
- , Xiong-yu Liao
- & Dun-hua Zhou
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Article
| Open AccessSerotonin limits generation of chromaffin cells during adrenal organ development
Adrenal glands are major organs regulating stress response., Melnikova et al., show that local release of serotonin limits adrenalin-producing cell number during rodent development, a mechanism which has implications for neuroblastoma development and stress-related maternal effects transmitted to progeny.
- Polina Kameneva
- , Victoria I. Melnikova
- & Igor Adameyko
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Article
| Open AccessFeasibility of whole genome and transcriptome profiling in pediatric and young adult cancers
Cancer whole-genome and transcriptome sequencing (cWGTS) has been challenging to implement in clinical settings. Here, the authors develop a workflow to deliver robust cWGTS analyses and reports within clinically-relevant timeframes for paediatric, adolescent and young adult solid tumour patients.
- N. Shukla
- , M. F. Levine
- & E. Papaemmanuil
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Article
| Open AccessEnvironmental cues from neural crest derivatives act as metastatic triggers in an embryonic neuroblastoma model
Neuroblastoma is characterised by cell types that feature mesenchymal like or sympathetic noradrenergic transcriptional profiles. Here, the authors show that exogenous factors secreted by sympathetic ganglion cells modulate these profiles, activating gene programs promoting the metastatic process.
- Dounia Ben Amar
- , Karine Thoinet
- & Valérie Castellani
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Article
| Open AccessHypoxia-activated neuropeptide Y/Y5 receptor/RhoA pathway triggers chromosomal instability and bone metastasis in Ewing sarcoma
Ewing sarcoma tumour cells frequently metastasize to the bone but the molecular mechanisms governing this process are not well understood. Here, the authors show that neuropeptide Y/Y5 receptor pathway is activated in the hypoxic tumour microenvironment, which results in cytokinesis defects and chromosomal instability, leading to bone invasion.
- Congyi Lu
- , Akanksha Mahajan
- & Joanna Kitlinska
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Article
| Open AccessDistinct genomic landscape of Chinese pediatric acute myeloid leukemia impacts clinical risk classification
The genomic landscape of pediatric acute myeloid leukemia (AML) has mostly been characterised for Western populations. Here, the authors identify potential driver alterations in Chinese pediatric AML, which differ from Western populations, and propose a prognostic risk classification model.
- Ting Liu
- , Jianan Rao
- & Shuhong Shen
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Article
| Open AccessSingle-cell transcriptomics identifies potential cells of origin of MYC rhabdoid tumors
Rhabdoid tumors (RT) are aggressive paediatric cancers with yet unknown cells of origin. Here, the authors establish genetically engineered mouse models of RT and, using single-cell RNA-seq and epigenomics, identify potential cells of origin for the SHH and MYC subtypes.
- Monika Graf
- , Marta Interlandi
- & Kornelius Kerl
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Article
| Open AccessSplicing is an alternate oncogenic pathway activation mechanism in glioma
Targeting genetic drivers of high grade diffuse glioma (HGG) has not improved patient survival, suggesting the involvement of other mechanisms. Here, across cancer types, the authors identify increased alternative splicing burden in cancer drivers compared to mutation rate as an alternative mechanism for activation of oncogenic pathways such as RAS/MAPK.
- Robert Siddaway
- , Scott Milos
- & Cynthia Hawkins
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Article
| Open AccessEZH2 depletion potentiates MYC degradation inhibiting neuroblastoma and small cell carcinoma tumor formation
While inhibition of the EZH2 methyltransferase activity has been used for targeting EZH2, its role in cancer progression remains unclear. Here, the authors use neuroblastoma and small cell lung carcinoma model systems and reveal the crosstalk between EZH2 and MYC(N) in the regulation of tumour formation.
- Liyuan Wang
- , Chan Chen
- & Guoliang Qing
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Article
| Open AccessAsthma reduces glioma formation by T cell decorin-mediated inhibition of microglia
Clinical studies have suggested a reduced incidence of brain tumors, including optic gliomas, in children with asthma. Here, in a mouse model of Neurofibromatosis type 1 associated low grade optic glioma, the authors show that experimental asthma induction decreases glioma formation and growth, resulting from T cell-dependent inhibition of microglia-mediated tumor support.
- Jit Chatterjee
- , Shilpa Sanapala
- & David H. Gutmann
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Article
| Open AccessBAF complexes drive proliferation and block myogenic differentiation in fusion-positive rhabdomyosarcoma
Rhabdomyosarcoma (RMS) is a pediatric malignancy of skeletal muscle lineage with an aggressive subtype caused by translocations involving PAX3- /PAX7-FOXO1 chimeric transcription factors. Here the authors show that the BRG1-containing BAF complex is overexpressed and acts largely independently of the PAX3-FOXO1 chimera on chromatin to result in a myogenic differentiation blockade in this malignancy.
- Dominik Laubscher
- , Berkley E. Gryder
- & Javed Khan
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Article
| Open AccessATR inhibition enables complete tumour regression in ALK-driven NB mouse models
Effective therapeutic options are still needed in neuroblastoma treatment. Here, the authors, through a comprehensive proteomics analysis, identify ATR as a potential therapeutic target of neuroblastoma and demonstrate the efficacy of the ATR inhibitor BAY1895344 in combination with the ALK tyrosine kinase inhibitor lorlatinib.
- Joanna Szydzik
- , Dan E. Lind
- & Ruth H. Palmer
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| Open AccessSpatial and temporal intratumour heterogeneity has potential consequences for single biopsy-based neuroblastoma treatment decisions
Neuroblastoma is a devastating tumour in children. Here, the authors analyse multi-region patient samples using genomics and transcriptomics, revealing temporal and spatial heterogeneity and questioning the reliability of single-biopsy based diagnostics.
- Karin Schmelz
- , Joern Toedling
- & Angelika Eggert
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Article
| Open AccessProteogenomic discovery of neoantigens facilitates personalized multi-antigen targeted T cell immunotherapy for brain tumors
Targeting tumor-associated antigens in paediatric medulloblastomas (MB) is challenging due to their low mutational burden. Here, the authors develop a sensitive proteogenomic approach to identify tumour specific neoantigens, which may enable personalised T cell immunotherapy in paediatric MB.
- Samuel Rivero-Hinojosa
- , Melanie Grant
- & Brian R. Rood
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| Open AccessA high-risk retinoblastoma subtype with stemness features, dedifferentiated cone states and neuronal/ganglion cell gene expression
Retinoblastoma is the most frequent intraocular paediatric malignancy whose molecular basis remains poorly understood. Here, the authors perform multi-omic analysis and identify two subtypes; one in a cone differentiated state and one more aggressive showing cone dedifferentiation and expressing neuronal markers.
- Jing Liu
- , Daniela Ottaviani
- & François Radvanyi
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Article
| Open AccessGenetic and epigenetic basis of hepatoblastoma diversity
While hepatoblastoma is the most common pediatric liver cancer, its molecular background has not been fully characterised. Here, the authors perform genomic and epigenomic profiling of 163 untreated pediatric liver tumours and suggest the upregulation of ASCL2 and methylation patterns of IGF2 promoters in driving hepatoblast carcinogenesis.
- Genta Nagae
- , Shogo Yamamoto
- & Eiso Hiyama
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Article
| Open AccessComprehensive molecular characterization of pediatric radiation-induced high-grade glioma
Radiation-induced high-grade gliomas (RIGs) are an incurable late complication of cranial radiation therapy. In the largest study to date, we report the results of DNA methylation profiling, RNA-Seq and genomic sequencing of 32 RIG tumors, and an in vitro drug screen in two RIG cell lines.
- John DeSisto
- , John T. Lucas Jr.
- & Adam L. Green
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| Open AccessSynthetic essentiality between PTEN and core dependency factor PAX7 dictates rhabdomyosarcoma identity
PTEN copy number loss is found in 25% of fusion-negative rhabdomyosarcomas (FN-RMS). Here, the authors use a Hedgehog-driven FN-RMS mouse model to show that PTEN loss drives the expression of core transcription factor PAX7 and its transcriptional axis, which determines FN-RMS tumour identity.
- Casey G. Langdon
- , Katherine E. Gadek
- & Mark E. Hatley
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Article
| Open AccessTherapeutic targeting of the PLK1-PRC1-axis triggers cell death in genomically silent childhood cancer
In this study, the authors show that that oncogenic hijacking of PRC1 sensitizes genomically stable Ewing sarcoma cells for PLK1 inhibition alone or in synergy with a microtubule-destabilizing drug via induction of cytokinesis defects, rendering PRC1 a promising, broadly applicable predictive biomarker
- Jing Li
- , Shunya Ohmura
- & Thomas G. P. Grünewald
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Article
| Open AccessSingle-nuclei transcriptomes from human adrenal gland reveal distinct cellular identities of low and high-risk neuroblastoma tumors
Childhood neuroblastoma can be separated into high and low risk groups, with prognosis depending on age at diagnosis. Here, the authors show that low and high risk neuroblastoma tumours are composed of different cell types with different malignancy potential.
- O. C. Bedoya-Reina
- , W. Li
- & S. Schlisio
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Article
| Open AccessRetinoblastoma from human stem cell-derived retinal organoids
Retinoblastoma is a heritable pediatric cancer driven by mutations in RB1. Here, the authors demonstrate the first patient derived model of retinoblastoma using iPSCs from patients with germline mutations in RB1.
- Jackie L. Norrie
- , Anjana Nityanandam
- & Michael A. Dyer
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Article
| Open AccessTSC2 regulates lysosome biogenesis via a non-canonical RAGC and TFEB-dependent mechanism
Tuberous sclerosis complex (TSC) is a multiorgan disease that can lead to hyperactive mTORC1 due to deficient TSC1 or TSC2 protein function. Here, the authors find that despite high mTORC1 activity, TFEB localizes to the nucleus and drives lysosomal gene expression via a non-canonical Rag-dependent mechanism.
- Nicola Alesi
- , Elie W. Akl
- & Elizabeth P. Henske
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| Open AccessPatient-derived models recapitulate heterogeneity of molecular signatures and drug response in pediatric high-grade glioma
Patient-derived xenografts provide a resource for basic and translational cancer research. Here, the authors generate multiple pediatric high-grade glioma xenografts, use omics technologies to show that they are representative of primary tumours and use them to assess therapeutic response.
- Chen He
- , Ke Xu
- & Suzanne J. Baker
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| Open AccessMultimodal analysis of cell-free DNA whole-genome sequencing for pediatric cancers with low mutational burden
Liquid biopsies enable minimally invasive applications for diagnosis and treatment monitoring. Here the authors analyse fragmentation patterns of circulating tumour DNA on multiple levels and develop a bioinformatic tool, LIQUORICE, to accurately detect and classify paediatric cancers with low mutational burden.
- Peter Peneder
- , Adrian M. Stütz
- & Eleni M. Tomazou
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Article
| Open AccessAn ALYREF-MYCN coactivator complex drives neuroblastoma tumorigenesis through effects on USP3 and MYCN stability
Neuroblastoma (NB) is often driven by MYCN amplification. Here, the authors show that the most frequent genetic lesion, gain of 17q21-ter in NB leads to overexpression of ALYREF, which forms a complex with MYCN, regulating MYCN stability via the deubiquitinating enzyme, USP3.
- Zsuzsanna Nagy
- , Janith A. Seneviratne
- & Glenn M. Marshall
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Article
| Open AccessThe transcriptional landscape of Shh medulloblastoma
Sonic Hedgehog medulloblastoma (Shh-MB) comprises four subtypes each with distinct clinical traits. Here the authors characterize the genome, transcriptome, and methylome of Shh-MB subtypes, revealing a complex fusion landscape and the molecular convergence of MYCN and cAMP signaling pathways.
- Patryk Skowron
- , Hamza Farooq
- & Michael D. Taylor
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| Open AccessAlternative lengthening of telomeres in childhood neuroblastoma from genome to proteome
Alternative lengthening of telomeres (ALT) is associated with a poor outcome in neuroblastoma. Here, the authors find that ALT is associated with mutated ATRX and/or reduced protein abundance, frequent telomeric repeat loci and heterochromatic telomeric chromatin.
- Sabine A. Hartlieb
- , Lina Sieverling
- & Frank Westermann
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Article
| Open AccessA pediatric brain tumor atlas of genes deregulated by somatic genomic rearrangement
The global impact of somatic structural variants (SSVs) on gene expression in childhood cancers is unclear. Here, the authors analyse cancer genome and RNA sequencing data of 854 pediatric brain tumours and report a landscape of genes deregulated by SSVs.
- Yiqun Zhang
- , Fengju Chen
- & Chad J. Creighton
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| Open AccessInteraction between SNAI2 and MYOD enhances oncogenesis and suppresses differentiation in Fusion Negative Rhabdomyosarcoma
Rhabdomyosarcomas are tumours blocked in myogenic differentiation, which despite the expression of master muscle regulatory factors, including MYOD, are unable to differentiate. Here, the authors show that SNAI2 is upregulated by MYOD through super enhancers, binds to MYOD target enhancers, and arrests differentiation.
- Silvia Pomella
- , Prethish Sreenivas
- & Myron S. Ignatius
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Article
| Open AccessEpigenetic activation of a RAS/MYC axis in H3.3K27M-driven cancer
Histone H3 at lysine 27 (H3K27M) is often mutated in cancer but its role in tumour initiation is unclear. Here, the authors generated a transgenic model expressing H3.3K27M from the Fabp7 gene promoter, demonstrating that H3.3K27M can initiate diverse tumorigesis on its own, acting through a RAS/MYC transcriptomic programme.
- Sanja Pajovic
- , Robert Siddaway
- & Cynthia Hawkins
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Article
| Open AccessCellular and gene signatures of tumor-infiltrating dendritic cells and natural-killer cells predict prognosis of neuroblastoma
Tumour-infiltrating lymphocytes play a crucial role in neuroblastoma, but their relationship to other immune cells is poorly understood. Here the authors identify the cellular and gene signatures of intratumoural dendritic cells and natural killer cells that predict the clinical outcome of neuroblastoma.
- Ombretta Melaiu
- , Marco Chierici
- & Doriana Fruci
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| Open AccessEnhancer hijacking determines extrachromosomal circular MYCN amplicon architecture in neuroblastoma
MYCN amplification is common in neuroblastomas. Here the authors analyse the MYCN amplicon structure and its epigenetic regulation by integrating short- and longread genomic and epigenomic data and find two classes of MYCN amplicons in neuroblastomas, one driven by local enhancers and the other by hijacking of distal regulatory elements.
- Konstantin Helmsauer
- , Maria E. Valieva
- & Richard P. Koche
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Article
| Open AccessCirculating tumour DNA from the cerebrospinal fluid allows the characterisation and monitoring of medulloblastoma
Non-invasive and precise methods are critical for monitoring paediatric brain cancers. Here the authors show that the molecular alterations and heterogeneity of paediatric medulloblastomas can be reliably detected in circulating tumour DNA from the cerebrospinal fluid – a routinely collected sample.
- Laura Escudero
- , Anna Llort
- & Joan Seoane
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Article
| Open AccessPan-neuroblastoma analysis reveals age- and signature-associated driver alterations
Genomic analysis of neuroblastoma has revealed important disease etiology. In this study, the authors assembled whole genome, exome and transcriptome data from over 700 neuroblastomas and identified molecular signatures correlated with age, and rare, potentially targetable variants overlooked in smaller cohorts.
- Samuel W. Brady
- , Yanling Liu
- & Jinghui Zhang
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Article
| Open AccessPhenotypic profiling with a living biobank of primary rhabdomyosarcoma unravels disease heterogeneity and AKT sensitivity
Patient-specific precision medicine approaches are important for future cancer therapies. Here, the authors show that functional drug profiling with Rhabdomyosarcoma cells isolated from PDX and primary patient tumors uncovers patient-specific vulnerabilities.
- Gabriele Manzella
- , Leonie D. Schreck
- & Marco Wachtel
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Article
| Open AccessWnt activation as a therapeutic strategy in medulloblastoma
The Wnt molecular subgroup of medulloblastoma is associated with better prognosis than the other molecular subgroups. Here, the authors show that activating Wnt signaling impairs tumor development and improves survival in Group 3 and Group 4 medulloblastoma preclinical models.
- Branavan Manoranjan
- , Chitra Venugopal
- & Sheila K. Singh
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Article
| Open AccessPediatric pan-central nervous system tumor analysis of immune-cell infiltration identifies correlates of antitumor immunity
Here, using methylCIBERSORT, the authors characterize the tumour-immune microenvironment of paediatric central nervous system (CNS) tumours and its association with tumour type and prognosis. These findings suggest that immuno-methylomic profiling may inform immunotherapy approaches in paediatric patients with CNS tumour.
- Yura Grabovska
- , Alan Mackay
- & Daniel Williamson
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Article
| Open AccessOncogenic hijacking of a developmental transcription factor evokes vulnerability toward oxidative stress in Ewing sarcoma
Ewing sarcoma is characterized by the fusion of EWSR1 and FLI1. Here, the authors show that EWSR1-FLI1 increases the activity of the developmental transcription factor SOX6, which promotes tumor growth but also increases sensitivity to oxidative stress.
- Aruna Marchetto
- , Shunya Ohmura
- & Thomas G. P. Grünewald
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Article
| Open AccessComprehensive germline genomic profiles of children, adolescents and young adults with solid tumors
Targeted therapies for solid tumors in children, adolescents, and young adults (C-AYA) lag behind that of adult carcinomas. Here, the authors study the germline genomic signatures of 1,507 C-AYA patients with solid tumors and find pathogenic/likely pathogenic germline variants in diverse genes of which 1/3 of these alterations are druggable.
- Sara Akhavanfard
- , Roshan Padmanabhan
- & Charis Eng
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Article
| Open AccessModeling germline mutations in pineoblastoma uncovers lysosome disruption-based therapy
Pineoblastoma is a rare pediatric cancer. Here, the authors present inactivation of Rb plus p53 via a WAP-Cre transgene induces metastatic pineoblastoma resembling human disease, and using this model, predict tricyclic antidepressants as a potential therapy for pineoblastoma, supported by their pre-clinical model.
- Philip E. D. Chung
- , Deena M. A. Gendoo
- & Eldad Zacksenhaus
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Article
| Open AccessAn organoid biobank for childhood kidney cancers that captures disease and tissue heterogeneity
Pre-clinical cell culture models capturing the heterogeneity of childhood kidney tumours are limited. Here, the authors establish and characterise an organoid biobank of tumour and matched normal organoid cultures from over 50 children with different subtypes of kidney cancer.
- Camilla Calandrini
- , Frans Schutgens
- & Jarno Drost
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Article
| Open AccessMYCN amplification and ATRX mutations are incompatible in neuroblastoma
In most cancers, mutations that lead to oncogene activation and tumor suppressor inactivation synergize to promote tumorigenesis. However, in neuroblastomas, MYCN amplification and ATRX mutations are mutually exclusive and incompatible.
- Maged Zeineldin
- , Sara Federico
- & Michael A. Dyer
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Article
| Open AccessForty-five patient-derived xenografts capture the clinical and biological heterogeneity of Wilms tumor
The progress in pre-clinical drug discovery for Wilms tumor (WT) is limited by a lack of disease models. Here, the authors develop 45 heterotopic WT patient-derived xenografts including several anaplastic models that recapitulate the biological heterogeneity of WT, and propose this as a resource for evaluating future therapeutics for WT.
- Andrew J. Murphy
- , Xiang Chen
- & Andrew M. Davidoff