image: (A) Experimental scheme for investigating the mechanisms underlying NB-BBM. (B) The sample overviews available for single-cell, whole genome sequencing, pathohistological, and survival data. (C) Workflow of a deep learning model for a multi-instance learning framework to predict NB-BBM.
Credit: Genes & Diseases
Neuroblastoma (NB), the most prevalent extracranial solid tumor among children, is characterized by a high rate of metastasis. The pathogenesis of NB with bone or bone marrow metastasis (NB-BBM) and its complex immune microenvironment remain poorly understood, posing challenges for effective risk prediction for BBM and limiting therapeutic strategies.
This research, published in the Genes & Diseases journal by a team from The Children's Hospital of Chongqing Medical University, highlights key genomic and single-cell transcriptomic alterations in NB-BBM, underscoring the significance of predictive pathology for NB-BBM and its role in understanding tumor onset, progression, and heterogeneity.
The researchers used a Swin-Transformer deep learning model to analyze 142 paraffin-embedded hematoxylin-eosin-stained tumor section images to predict NB-BBM occurrence, achieving a classification accuracy exceeding 85%. In parallel, single-cell transcriptomics identified a tumor cell subpopulation (NB3) and two tumor-associated macrophage (TAM) subpopulations (SPP1+ TAMs and IGHM+ TAMs) closely associated with BBM progression. Interestingly, findings reveal that oxidative phosphorylation (OXPHOS) also plays a crucial role in BBM development.
Additionally, this study highlighted transketolase (TKT) as a crucial metabolic molecule linked to BBM. The researchers showed that the TKT gene was strongly associated with the clinical features of NB patients, especially in the BBM group. Functional experiments validated TKT’s involvement in malignant behavior, while pathway enrichment analysis showed correlations between high TKT expression and cell cycle activity.
Moreover, expression analysis of immune checkpoint genes CD274, LAG3, and TIGIT revealed their significant upregulation in NB-BBM, suggesting potential targets for antibody-based immunotherapies. Furthermore, immunohistochemical validation demonstrated a pronounced expression of PD-L1 in NB-BBM, indicating its potential as a biomarker.
Although this research provides a predictive model for NB-BBM risk assessment, it has certain limitations, including the need for multicenter validation of the predictive model and prospective studies to confirm clinical utility. Despite these challenges, this study offers a pathodiagnostic prediction for the risk of NB-BBM, enhances other imaging diagnoses, and elucidates the cellular heterogeneity of initial, progressive, and distant metastatic sites in NB.
Reference
Title of the original paper: Integrated multi-omics characterization of neuroblastoma with bone or bone marrow metastasis
Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.
DOI: https://doi.org/10.1016/j.gendis.2024.101511
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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.
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