Cancer plasticity in therapy resistance: Mechanisms and novel strategies

Drug Resistance Updates, Год журнала: 2024, Номер 76, С. 101114 - 101114

Опубликована: Июнь 22, 2024

Язык: Английский

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Genetic Risk Profiling Reveals Altered Glycosyltransferase Expression as a Predictor for Patient Outcome in Neuroblastoma

Journal of Clinical Medicine, Год журнала: 2025, Номер 14(2), С. 527 - 527

Опубликована: Янв. 15, 2025

Background/Objectives: Neuroblastoma is a highly aggressive pediatric cancer that arises from immature nerve cells and exhibits broad spectrum of clinical presentations. While low- intermediate-risk neuroblastomas often have favorable outcomes, high-risk are associated with poor prognosis significant treatment challenges. The complex genetic networks driving these cases remain poorly understood. This study aims to investigate differences in gene expression patterns may contribute disease outcomes. Methods: We employed an silico approach analyze cohort 493 neuroblastoma tumor samples underwent mRNA sequencing (GSE49711). dataset was reanalyzed depth non-hypothesis-driven identify the regulatory mechanisms prognosis. Results: By exploring global integration parameters, we stratified into two groups distinct profiles. MYCN amplification emerged as major driver not only but also specific patterns. Notably, tumors exhibited strong regulation immune response genes less infiltration, suggesting potential evasion. However, while observed minor changes checkpoint expression, there modulation glycosyltransferase MYCN-amplified tumors. Using this information, were able construct risk profile based on 12 glycosylation-related genes, which correlates survival outcomes patients. Conclusions: highlights role through genes. Based finding, developed

Язык: Английский

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Emerging clinical and research approaches in targeted therapies for high-risk neuroblastoma

Frontiers in Oncology, Год журнала: 2025, Номер 15

Опубликована: Март 4, 2025

Neuroblastoma is a pediatric cancer that originates from neural crest cells and the most common extracranial solid tumor in children under five years of age. While low-risk neuroblastoma often regresses spontaneously, high-risk poses significant clinical challenge. Recent advances understanding neuroblastoma’s molecular mechanisms have led to development targeted therapies aim selectively inhibit specific pathways involved growth progression, improving patient outcomes while minimizing side effects. This review provides comprehensive biology emerging therapeutic strategies. Key topics include (a) immunotherapies immunotargets, (b) non-coding RNAs (long RNA, microRNA, circular RNA), (c) biomarkers pathways, (d) limitations future directions.

Язык: Английский

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Interactions between LAMP3+ dendritic cells and T-cell subpopulations promote immune evasion in papillary thyroid carcinoma

Journal for ImmunoTherapy of Cancer, Год журнала: 2024, Номер 12(5), С. e008983 - e008983

Опубликована: Май 1, 2024

The incidence of papillary thyroid cancer (PTC) continues to rise all over the world, 10-15% patients have a poor prognosis. Although immunotherapy has been applied in clinical practice, its therapeutic efficacy remains far from satisfactory, necessitating further investigation mechanism PTC immune remodeling and exploration novel treatment targets. This study conducted single-cell RNA sequencing (scRNA-seq) analysis using 18 surgical tissue specimens procured 14 diagnosed with adjacent tissues, non-progressive or progressive PTC. Key findings were authenticated through spatial transcriptomics sequencing, immunohistochemistry, multiplex an independent bulk RNA-seq data set containing 502 samples. A total 151,238 individual cells derived underwent scRNA-seq analysis. We found that exhibits following characteristics: significant decrease overall cells, enhanced evasion tumor disrupted antigen presentation function. Moreover, we identified subpopulation lysosomal associated membrane protein 3 (LAMP3+) dendritic (DCs) exhibiting heightened infiltration advanced T stage prognosis LAMP3+ DCs promote CD8+ exhaustion (mediated by NECTIN2-TIGIT) increase abundance regulatory chemokine (C-C motif) ligand 17 (CCL17)-chemokine receptor 4 (CCR4)) establishing immune-suppressive microenvironment. Ultimately, unveiled facilitate retention within microenvironment NECTIN3-NECTIN2 interactions, thereby rendering more susceptible evasion. Our expound valuable insights into role interaction between T-cell subpopulations offer new effective ideas strategies for

Язык: Английский

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The neuroblastoma tumor microenvironment: From an in-depth characterization towards novel therapies

EJC Paediatric Oncology, Год журнала: 2024, Номер 3, С. 100161 - 100161

Опубликована: Апрель 7, 2024

Neuroblastoma is a cancer of the sympathetic nervous system that develops in young children, either as low-risk or high-risk disease. The tumor microenvironment (TME) now recognized an important player ecosystem may promote drug resistance and immune escape. Targeting TME combination with therapies directly targeting cells therefore represents interesting strategy to prevent emergence improve patient's outcome. development such strategies however requires in-depth understanding landscape, due its high complexity intra inter-tumoral heterogeneity. Various approaches have been used last years characterize non-immune cell populations present tumors neuroblastoma patients, both quantitatively qualitatively, particular use single-cell transcriptomics. It anticipated near future, genomic information will contribute precise approach therapy neuroblastoma.Deciphering mechanisms interaction between stromal key identify novel therapeutic combinations. Over decade, numerous vitro studies vivo pre-clinical experiments immune-competent immune-deficient models identified circumvent Some these formed basis for early phase I II clinical trials children recurrent refractory neuroblastoma. This review summarizes recently published data on characterization landscape various cellular components, molecules pathways activated result tumor-host interactions.

Язык: Английский

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Identification and characterization of chemotherapy resistant high-risk neuroblastoma persister cells

Cancer Discovery, Год журнала: 2024, Номер unknown, С. OF1 - OF20

Опубликована: Июль 31, 2024

Abstract Relapse rates in high-risk neuroblastoma remain exceedingly high. The malignant cells that are responsible for relapse have not been identified, and mechanisms of therapy resistance poorly understood. In this study, we used single-nucleus RNA sequencing bulk whole-genome to identify characterize the residual persister survive chemotherapy from a cohort 20 matched diagnosis definitive surgery tumor samples patients treated with induction chemotherapy. We show share common escape, including suppression MYC(N) activity activation NFκB signaling, latter is further enhanced by cell–cell communication between microenvironment. Overall, our work dissects transcriptional landscape cellular persistence paves way development new therapeutic strategies prevent disease relapse. Significance: Approximately 50% die relapsed refractory disease. identified likely contribute discovered key signaling pathways mediate persistence. Inhibition these their downstream effectors postulated eliminate

Язык: Английский

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CSI-GEP: A GPU-based unsupervised machine learning approach for recovering gene expression programs in atlas-scale single-cell RNA-seq data

Cell Genomics, Год журнала: 2025, Номер 5(1), С. 100739 - 100739

Опубликована: Янв. 1, 2025

Exploratory analysis of single-cell RNA sequencing (scRNA-seq) typically relies on hard clustering over two-dimensional projections like uniform manifold approximation and projection (UMAP). However, such methods can severely distort the data have many arbitrary parameter choices. Methods that model scRNA-seq as non-discrete "gene expression programs" (GEPs) better preserve data's structure, but currently, they are often not scalable, consistent across repeated runs, lack an established method for choosing key parameters. Here, we developed a GPU-based unsupervised learning approach, "consensus scalable inference gene (CSI-GEP). We show CSI-GEP recover ground truth GEPs in real simulated atlas-scale datasets, significantly outperforming cutting-edge methods, including GPT-based neural networks. applied to whole mouse brain atlas 2.2 million cells, disentangling endothelial cell types missed by other integrated human tumors lines, discovering mesenchymal-like unique cancer cells growing culture.

Язык: Английский

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Pan-cancer human brain metastases atlas at single-cell resolution

Cancer Cell, Год журнала: 2025, Номер unknown

Опубликована: Апрель 1, 2025

Язык: Английский

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CAR T-cell-mediated delivery of bispecific innate immune cell engagers for neuroblastoma

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Авг. 21, 2024

Novel chimeric antigen receptor (CAR) T-cell approaches are needed to improve therapeutic efficacy in solid tumors. High-risk neuroblastoma is an aggressive pediatric tumor that expresses cell-surface GPC2 and GD2 with a microenvironment infiltrated by CD16a-expressing innate immune cells. Here we engineer T-cells express GPC2-directed CAR simultaneously secrete bispecific cell engager (BiCE) targeting both CD16a. In vitro, GPC2.CAR-GD2.BiCE induce GPC2-dependent cytotoxicity GD2.BiCE promotes GD2-dependent activation of antitumor immunity. vivo, locally deliver increase intratumor retention NK-cells. mice bearing patient-derived xenografts reconstituted human cells, GD2.BiCEs enhance GPC2.CAR efficacy. A CAR.BiCE strategy should be considered for histologies where escape limits efficacy, especially tumors like

Язык: Английский

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Chemotherapy induces myeloid-driven spatial T-cell exhaustion in ovarian cancer

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Март 20, 2024

To uncover the intricate, chemotherapy-induced spatiotemporal remodeling of tumor microenvironment, we conducted integrative spatial and molecular characterization 97 high-grade serous ovarian cancer (HGSC) samples collected before after chemotherapy. Using single-cell analyses, identify increasingly versatile immune cell states, which form spatiotemporally dynamic microcommunities at tumor-stroma interface. We demonstrate that chemotherapy triggers redistribution exhaustion CD8+ T cells due to prolonged antigen presentation by macrophages, both within interconnected myeloid networks termed "Myelonets" stroma Single-cell transcriptomics identifies prominent TIGIT-NECTIN2 ligand-receptor interactions induced a functional patient-derived immuno-oncology platform, show CD8+T-cell activity can be boosted combining checkpoint blockade with Our discovery myeloid-driven T-cell paves way for novel immunotherapeutic strategies unleash T-cell-mediated anti-tumor immunity in HGSC.

Язык: Английский

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