Stemness Correlates Inversely with MHC Class I Expression in Pediatric Small Round Blue Cell Tumors DOI Open Access
Linda Müller, Maik Kschischo, Christian Vokuhl

et al.

Cancers, Journal Year: 2022, Volume and Issue: 14(15), P. 3584 - 3584

Published: July 22, 2022

Recently, immunotherapeutic approaches have become a feasible option for subset of pediatric cancer patients. Low MHC class I expression hampers the use immunotherapies relying on antigen presentation. A well-established stemness score (mRNAsi) was determined using bulk transcriptomes 1134 small round blue cell tumors. Interestingly, gene (HLA-A/-B/-C) correlated negatively with mRNAsi throughout all diagnostic entities: neuroblastomas (NB) (n = 88, r −0.41, p < 0.001), Ewing’s sarcoma family tumors (ESFT) 117, −0.46, rhabdomyosarcomas (RMS) 158, −0.5, Wilms (WT) 224, −0.39, and central nervous system-primitive neuroectodermal CNS-PNET (r −0.49, exception medulloblastoma (MB) 76, −0.24, 0.06). The negative correlation independent clinical features in NB, RMS, WT. In NB WT, increased tumor stage. RMS patients high abundant CD8 T cells showed prolonged overall survival 148, 0.004). Possibly, low are remnants prenatal tumorigenesis from multipotent precursor cells. Further studies needed to assess usefulness as predictive markers.

Language: Английский

Cellular development and evolution of the mammalian cerebellum DOI Creative Commons
Mari Sepp, Kevin Leiss, Florent Murat

et al.

Nature, Journal Year: 2023, Volume and Issue: 625(7996), P. 788 - 796

Published: Nov. 29, 2023

The expansion of the neocortex, a hallmark mammalian evolution

Language: Английский

Citations

63
Compartments in medulloblastoma with extensive nodularity are connected through differentiation along the granular precursor lineage DOI Creative Commons
David R. Ghasemi, Konstantin Okonechnikov, Anne Rademacher

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Jan. 8, 2024

Medulloblastomas with extensive nodularity are cerebellar tumors characterized by two distinct compartments and variable disease progression. The mechanisms governing the balance between proliferation differentiation in MBEN remain poorly understood. Here, we employ a multi-modal single cell transcriptome analysis to dissect this process. In internodular compartment, identify proliferating granular neuronal precursor-like malignant cells, along stromal, vascular, immune cells. contrast, nodular compartment comprises postmitotic, neuronally differentiated Both connected through an intermediate stage resembling actively migrating CGNPs. Notably, also discover astrocytic-like found proximity cells at transition zone compartments. Our study sheds light on spatial tissue organization its link developmental trajectory, resulting more benign tumor phenotype. This integrative approach holds promise explore intercompartmental interactions other cancers varying histology.

Language: Английский

Citations

10
Heterogeneity and tumoral origin of medulloblastoma in the single-cell era DOI Creative Commons

Hui Sheng,

Haotai Li,

Han Zeng

et al.

Oncogene, Journal Year: 2024, Volume and Issue: 43(12), P. 839 - 850

Published: Feb. 14, 2024

Abstract Medulloblastoma is one of the most common malignant pediatric brain tumors derived from posterior fossa. The current treatment includes maximal safe surgical resection, radiotherapy, whole cranio-spinal radiation and adjuvant with chemotherapy. However, it can only limitedly prolong survival time severe side effects relapse. Defining intratumoral heterogeneity, cellular origin identifying interaction network within tumor microenvironment are helpful for understanding mechanisms medulloblastoma tumorigenesis Due to technological limitations, heterogeneity have not been fully understood. Recently, emergence single-cell technology has provided a powerful tool achieving goal tumorigenesis. Several studies demonstrated each subtype utilizing RNA-seq, which uncovered before using conventional technologies. In this review, we present an overview progress in discuss novel findings age

Language: Английский

Citations

9
Developmental basis of SHH medulloblastoma heterogeneity DOI Creative Commons
Maxwell P. Gold, Winnie Ong,

Andrew M. Masteller

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Jan. 8, 2024

Abstract Many genes that drive normal cellular development also contribute to oncogenesis. Medulloblastoma (MB) tumors likely arise from neuronal progenitors in the cerebellum, and we hypothesized heterogeneity observed MBs with sonic hedgehog (SHH) activation could be due differences developmental pathways. To investigate this question, here perform single-nucleus RNA sequencing on highly differentiated SHH extensively nodular histology malignant cells resembling each stage of canonical granule neuron development. Through innovative computational approaches, connect these results published datasets find some established molecular subtypes MB appear arrested at different stages. Additionally, using multiplexed proteomic imaging MALDI mass spectrometry, identify distinct histological metabolic profiles for tumors. Our approaches are applicable understanding interplay between differentiation other cancers can provide important insights design targeted therapies.

Language: Английский

Citations

7
Multiparametric MRI-Based Interpretable Radiomics Machine Learning Model Differentiates Medulloblastoma and Ependymoma in Children: A Two-Center Study DOI Creative Commons

Yasen Yimit,

Parhat Yasin,

Abudouresuli Tuersun

et al.

Academic Radiology, Journal Year: 2024, Volume and Issue: 31(8), P. 3384 - 3396

Published: March 20, 2024

Language: Английский

Citations

6
Amplification of the PLAG-family genes—PLAGL1 and PLAGL2—is a key feature of the novel tumor type CNS embryonal tumor with PLAGL amplification DOI Creative Commons
Michaela‐Kristina Keck, Martin Sill,

Andrea Wittmann

et al.

Acta Neuropathologica, Journal Year: 2022, Volume and Issue: 145(1), P. 49 - 69

Published: Nov. 27, 2022

Abstract Pediatric central nervous system (CNS) tumors represent the most common cause of cancer-related death in children aged 0–14 years. They differ from their adult counterparts, showing extensive clinical and molecular heterogeneity as well a challenging histopathological spectrum that often impairs accurate diagnosis. Here, we use DNA methylation-based CNS tumor classification combination with copy number, RNA-seq, ChIP-seq analysis to characterize newly identified type. In addition, report histology, patient characteristics, survival data this We describe biologically distinct pediatric type ( n = 31 cases) is characterized by focal high-level amplification resultant overexpression either PLAGL1 or PLAGL2 , an absence recurrent genetic alterations characteristic other types. Both genes act transcription factors for regulatory subset imprinted (IGs), components Wnt/β-Catenin pathway, potential drug targets RET CYP2W1 which are also specifically overexpressed A derived PLAGL-specific gene expression signature indicates dysregulation imprinting control differentiation/development. These occurred throughout neuroaxis including cerebral hemispheres, cerebellum, brainstem, were predominantly composed primitive embryonal-like cells lacking robust markers glial neuronal differentiation (e.g., GFAP, OLIG2, synaptophysin). Tumors typically diagnosed during adolescence (median age 10.5 years), whereas those early childhood 2 years). The 10-year overall was 66% -amplified tumors, 25% 18% male patients, 82% female patients. summary, new PLAGL1/2 occurs infants toddlers ) adolescents consider best classified embryonal associated intermediate survival. cell origin optimal treatment strategies remain be defined.

Language: Английский

Citations

21
Advances in molecular prognostication and treatments in ependymoma DOI

Emma Bakes,

Richard P. Cheng,

Noralyn Mañucat-Tan

et al.

Journal of Neuro-Oncology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 6, 2025

Language: Английский

Citations

0
High-resolution digital dissociation of brain tumors with deep multimodal autoencoder DOI Creative Commons

Jiao Sun,

Yue Pan, Tong Lin

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 3, 2025

Abstract Single-cell technologies enable high-resolution, multi-dimensional analysis of molecular profiles in cancer biology but face challenges related to low coverage and cell annotation. The inherent hetero-geneity complexity brain tumors may hinder large-scale single multi-omic profiling. An efficient alternative is digital dissociation, which involves quantifying abundance purifying bulk samples at high resolution. However, most existing tools for resolving transcriptomes using scRNA-seq as a reference are not easily transferred other omics (e.g., chromatin accessibility, DNA methylation, protein) due ambiguous markers. Here, we introduce MODE, novel multimodal autoencoder neural network designed jointly recover personalized estimate cellular compositions. MODE the first algorithm trained on pseudo-bulk multi-omics derived from an external individualized non-RNA panel constructed target tumors. accuracy was evaluated through extensive simulation study, generated realistic data distinct tissue types. outperformed deconvolution pipelines with superior generalizability. Additionally, high-resolution purified by showed strong fidelity enhanced power detect differentially expressed genes. We applied methylome-transcriptome two independent tumor cohorts, revealing modality-specific landscapes pediatric medul-loblastoma (MB) adult glioblastoma (GBM). In MB tumors, accurately predicted composition embryonal lineage cells their marker genes expression. GBM, deconvoluted revealed increased myeloid associated poorer event-free survival. Overall, dissociation unravels origins, evolution, prognosis offering powerful tool state resolution without sequencing. pipeline freely available https://github.com/jsuncompubio/MODE .

Language: Английский

Citations

0
Therapeutic approaches for targeting the pediatric brain tumor microenvironment DOI
Caroline A Stockwell, Morrent Thang, David E. Kram

et al.

Drug Delivery and Translational Research, Journal Year: 2025, Volume and Issue: unknown

Published: April 21, 2025

Language: Английский

Citations

0
Oncogene aberrations drive medulloblastoma progression, not initiation DOI Creative Commons
Konstantin Okonechnikov, Piyush Joshi, Verena Körber

et al.

Nature, Journal Year: 2025, Volume and Issue: unknown

Published: May 7, 2025

Abstract Despite recent advances in understanding disease biology, treatment of group 3/4 medulloblastoma remains a therapeutic challenge paediatric neuro-oncology 1 . Bulk-omics approaches have identified considerable intertumoural heterogeneity medulloblastoma, including the presence clear single-gene oncogenic drivers only subset cases, whereas most large-scale copy number aberrations prevail 2,3 However, intratumoural heterogeneity, role oncogene aberrations, and broad variation tumour evolution resistance remain poorly understood. To dissect this interplay, we used single-cell technologies (single-nucleus RNA sequencing (snRNA-seq), single-nucleus assay for transposase-accessible chromatin with high-throughput (snATAC-seq) spatial transcriptomics) on cohort known alterations oncogenes MYC , MYCN PRDM6 We show that chromosomal are early tumour-initiating events, events arise late typically subclonal, but can become clonal upon progression to drive further development therapy resistance. Spatial transcriptomics shows subclones mostly interspersed across tissue, segregation is also present. Using population genetics model, estimate initiation cerebellar unipolar brush cell lineage starting from first gestational trimester. Our findings demonstrate how be applied detection diagnosis fatal disease.

Language: Английский

Citations

0