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Article
| Open Access
Preneoplastic liver colonization by 11p15.5 altered mosaic cells in young children with hepatoblastoma
Paediatric liver cancer is rare, and often associated with a predisposition syndrome. Here, the authors show that 11p15.5 mosaic alteration in the liver is a pre-neoplastic lesion associated with hepatoblastoma, and spatial transcriptomics together with single-nucleus RNAseq identify a an altered zonation in the liver of these patients.
- Jill Pilet
- , Theo Z. Hirsch
- & Jessica Zucman-Rossi
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Article
| Open Access
Imaging and multi-omics datasets converge to define different neural progenitor origins for ATRT-SHH subgroups
Atypical teratoid rhabdoid tumors (ATRT) are divided into three molecular subgroups, which could have different lineages of origin. Here, the authors use tumour imaging, multi-omics and genetically engineered mouse models to determine the anatomical region and cell lineage of origin of ATRT subtypes.
- María-Jesús Lobón-Iglesias
- , Mamy Andrianteranagna
- & Franck Bourdeaut
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Article
| Open Access
Integrated genomic analysis reveals aberrations in WNT signaling in germ cell tumors of childhood and adolescence
Genomic landscape studies of malignant germ cell tumors (GCTs) that occur in children, adolescents and young adults are limited. Here the authors perform multi-omics profiling of different types of GCTs across the age spectrum from 0–24 years and show that WNT signalling pathway is activated in GCTs and is associated with poor clinical outcomes.
- Lin Xu
- , Joshua L. Pierce
- & James F. Amatruda
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Article
| Open Access
Environmental 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 Access
Single-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 Access
Genetic 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 Access
Synthetic 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 Access
Schwann cell plasticity regulates neuroblastic tumor cell differentiation via epidermal growth factor-like protein 8
Schwann cells (SCs) can acquire a repair phenotype following nerve injury. Here, the authors show that stromal SCs in ganglioneuromas express nerve-repair genes. Importantly, neuroblastoma cells respond to repair-related SCs increasing neuronal differentiation and reducing proliferation via EGFL8.
- Tamara Weiss
- , Sabine Taschner-Mandl
- & Inge M. Ambros
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Article
| Open Access
Somatic mutations and single-cell transcriptomes reveal the root of malignant rhabdoid tumours
Malignant rhabdoid tumours (MRT) have been suggested to originate in the ectoderm-derived neural crest. Here, the authors analyse MRTs using phylogenetics, scRNA-seq, and patient-derived organoids; they find evidence for an MRT origin in the neural crest lineage and suggest differentiation treatment with HDAC/mTOR inhibitors.
- Lars Custers
- , Eleonora Khabirova
- & Jarno Drost
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Article
| Open Access
Alternative 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 Access
Forty-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
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Article
| Open Access
JMJD6 is a tumorigenic factor and therapeutic target in neuroblastoma
Although the gain in chromosome 17q21-ter is commonly associated with neuroblastoma, it is not clear which gene of this region mediates tumorigenesis. Here, the authors are showing that JMJD6, which locates in that region, is a neuroblastoma tumorigenic factor.
- Matthew Wong
- , Yuting Sun
- & Tao Liu
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Article
| Open Access
Transcriptome 3′end organization by PCF11 links alternative polyadenylation to formation and neuronal differentiation of neuroblastoma
In gene regulation, diversification at the transcriptome 3′end is linked to differentiation and dedifferentiation. Here, the authors discover extensive transcriptome 3′end-alterations in neuroblastoma, regulated by PCF11, and provide an interactive data repository of transcriptome-wide alternative polyadenylation.
- Anton Ogorodnikov
- , Michal Levin
- & Sven Danckwardt
A human neural crest model reveals the developmental impact of neuroblastoma-associated chromosomal aberrations