A clinically applicable connectivity signature for glioblastoma includes the tumor network driver CHI3L1 DOI Creative Commons
Ling Hai, Dirk C. Hoffmann, Robin J. Wagener

et al.

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

Published: Feb. 6, 2024

Abstract Tumor microtubes (TMs) connect glioma cells to a network with considerable relevance for tumor progression and therapy resistance. However, the determination of TM-interconnectivity in individual tumors is challenging impact on patient survival unresolved. Here, we establish connectivity signature from single-cell RNA-sequenced (scRNA-Seq) xenografted primary glioblastoma (GB) using dye uptake methodology, validate it recording cellular calcium epochs clinical correlations. Astrocyte-like mesenchymal-like GB have highest scores scRNA-sequenced patient-derived xenografts samples. In large cohorts, TM-network correlates mesenchymal subtype dismal survival. CHI3L1 gene expression serves as robust molecular marker functionally influences TM networks. The allows insights into brain biology, provides proof-of-principle that cell TM-connectivity relevant patients’ prognosis, prognostic biomarker.

Language: Английский

Glioblastoma hijacks neuronal mechanisms for brain invasion DOI Creative Commons
Varun Venkataramani, Yvonne Yang, Marc C. Schubert

et al.

Cell, Journal Year: 2022, Volume and Issue: 185(16), P. 2899 - 2917.e31

Published: July 31, 2022

Language: Английский

Citations

345
Cancer neuroscience: State of the field, emerging directions DOI Creative Commons
Frank Winkler, Humsa S. Venkatesh, Moran Amit

et al.

Cell, Journal Year: 2023, Volume and Issue: 186(8), P. 1689 - 1707

Published: April 1, 2023

The nervous system governs both ontogeny and oncology. Regulating organogenesis during development, maintaining homeostasis, promoting plasticity throughout life, the plays parallel roles in regulation of cancers. Foundational discoveries have elucidated direct paracrine electrochemical communication between neurons cancer cells, as well indirect interactions through neural effects on immune stromal cells tumor microenvironment a wide range malignancies. Nervous system-cancer can regulate oncogenesis, growth, invasion metastatic spread, treatment resistance, stimulation tumor-promoting inflammation, impairment anti-cancer immunity. Progress neuroscience may create an important new pillar therapy.

Language: Английский

Citations

205
The diversified role of mitochondria in ferroptosis in cancer DOI Creative Commons
Yue Liu,

Shi-Ping Lu,

Lei‐Lei Wu

et al.

Cell Death and Disease, Journal Year: 2023, Volume and Issue: 14(8)

Published: Aug. 14, 2023

Abstract Ferroptosis is a form of regulated cell death induced by iron-dependent lipid peroxidation, and it has been studied extensively since its discovery in 2012. Induced iron overload ROS accumulation, ferroptosis modulated various cellular metabolic signaling pathways. The GSH-GPX4 pathway, the FSP1-CoQ10 GCH1-BH4 DHODH-CoQH2 system sex hormones suppress ferroptosis. Mitochondrial metabolism regulates mitochondria also undergo morphological change during ferroptosis, these changes include increased membrane density reduced mitochondrial cristae. Moreover, energy oxidative phosphorylation ATP production rates lead to decrease glycolysis rate. In addition, excessive stress induces irreversible damage mitochondria, diminishing organelle integrity. production, potential, fusion fission, mitophagy function Notably, some inhibitors target mitochondria. major mechanism for associated with progression cancer. Metastasis-prone or metastatic cancer cells are more susceptible Inducing tumor shows very promising potential treating drug-resistant cancers. this review, we present brief retrospect characteristics then discuss regulation highlight unique role played cells. Furthermore, explain how functions as double-edged sword well novel therapies aimed at selectively manipulating eradication.

Language: Английский

Citations

154
The neuroscience of cancer DOI
Rebecca Mancusi, Michelle Monje

Nature, Journal Year: 2023, Volume and Issue: 618(7965), P. 467 - 479

Published: June 14, 2023

Language: Английский

Citations

127
Transcriptome analysis reveals tumor microenvironment changes in glioblastoma DOI Creative Commons
Youri Hoogstrate, Kaspar Draaisma, Santoesha A Ghisai

et al.

Cancer Cell, Journal Year: 2023, Volume and Issue: 41(4), P. 678 - 692.e7

Published: March 9, 2023

A better understanding of transcriptional evolution IDH-wild-type glioblastoma may be crucial for treatment optimization. Here, we perform RNA sequencing (RNA-seq) (n = 322 test, n 245 validation) on paired primary-recurrent resections patients treated with the current standard care. Transcriptional subtypes form an interconnected continuum in a two-dimensional space. Recurrent tumors show preferential mesenchymal progression. Over time, hallmark genes are not significantly altered. Instead, tumor purity decreases over time and is accompanied by co-increases neuron oligodendrocyte marker and, independently, tumor-associated macrophages. decrease observed endothelial genes. These composition changes confirmed single-cell RNA-seq immunohistochemistry. An extracellular matrix-associated gene set increases at recurrence bulk, RNA, immunohistochemistry indicate it expressed mainly pericytes. This signature associated worse survival recurrence. Our data demonstrate that glioblastomas evolve microenvironment (re-)organization rather than molecular cells.

Language: Английский

Citations

123
Glioma synapses recruit mechanisms of adaptive plasticity DOI Creative Commons
Kathryn R. Taylor, Tara Barron,

Alexa Hui

et al.

Nature, Journal Year: 2023, Volume and Issue: 623(7986), P. 366 - 374

Published: Nov. 1, 2023

Abstract The role of the nervous system in regulation cancer is increasingly appreciated. In gliomas, neuronal activity drives tumour progression through paracrine signalling factors such as neuroligin-3 and brain-derived neurotrophic factor 1–3 (BDNF), also electrophysiologically functional neuron-to-glioma synapses mediated by AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors 4,5 . consequent glioma cell membrane depolarization proliferation 4,6 healthy brain, activity-regulated secretion BDNF promotes adaptive plasticity synaptic connectivity 7,8 strength 9–15 Here we show that malignant exhibit similar regulated BDNF. Signalling receptor tropomyosin-related kinase B 16 (TrkB) to CAMKII, trafficking membrane, resulting increased amplitude glutamate-evoked currents cells. Linking growth, graded optogenetic control potential demonstrates greater depolarizing current proliferation. This potentiation shares mechanistic features with 17–22 contributes memory learning brain 23–26 BDNF–TrkB regulates number synapses. Abrogation from microenvironment or loss TrkB expression robustly inhibits progression. Blocking genetically pharmacologically abrogates these effects on substantially prolongs survival xenograft models paediatric glioblastoma diffuse intrinsic pontine glioma. Together, findings indicate augments

Language: Английский

Citations

95
Macrophage-mediated myelin recycling fuels brain cancer malignancy DOI Creative Commons
Daan J. Kloosterman, Johanna Erbani,

Menno Boon

et al.

Cell, Journal Year: 2024, Volume and Issue: 187(19), P. 5336 - 5356.e30

Published: Aug. 12, 2024

Tumors growing in metabolically challenged environments, such as glioblastoma the brain, are particularly reliant on crosstalk with their tumor microenvironment (TME) to satisfy high energetic needs. To study intricacies of this metabolic interplay, we interrogated heterogeneity TME using single-cell and multi-omics analyses identified rewired tumor-associated macrophage (TAM) subpopulations pro-tumorigenic properties. These TAM subsets, termed lipid-laden macrophages (LLMs) reflect cholesterol accumulation, epigenetically rewired, display immunosuppressive features, enriched aggressive mesenchymal subtype. Engulfment cholesterol-rich myelin debris endows subsets TAMs acquire an LLM phenotype. Subsequently, LLMs directly transfer myelin-derived lipids cancer cells LXR/Abca1-dependent manner, thereby fueling heightened demands glioblastoma. Our work provides in-depth understanding immune-metabolic interplay during progression, laying a framework unveil targetable vulnerabilities

Language: Английский

Citations

38
A prognostic neural epigenetic signature in high-grade glioma DOI Creative Commons
Richard Drexler, Robin Khatri, Thomas Sauvigny

et al.

Nature Medicine, Journal Year: 2024, Volume and Issue: 30(6), P. 1622 - 1635

Published: May 17, 2024

Abstract Neural–tumor interactions drive glioma growth as evidenced in preclinical models, but clinical validation is limited. We present an epigenetically defined neural signature of glioblastoma that independently predicts patients’ survival. use reference signatures cells to deconvolve tumor DNA and classify samples into low- or high-neural tumors. High-neural glioblastomas exhibit hypomethylated CpG sites upregulation genes associated with synaptic integration. Single-cell transcriptomic analysis reveals a high abundance malignant stemcell-like glioblastoma, primarily the lineage. These are further classified neural-progenitor-cell-like, astrocyte-like oligodendrocyte-progenitor-like, alongside oligodendrocytes excitatory neurons. In line these findings, engender neuron-to-glioma synapse formation vitro vivo show unfavorable survival after xenografting. patients, decreased overall progression-free tumors also increased functional connectivity magnetencephalography resting-state magnet resonance imaging can be detected via analytes brain-derived neurotrophic factor plasma. The prognostic importance was validated patients diagnosed diffuse midline glioma. Our study presents high-grade gliomas prognostically relevant. likely require maximized surgical resection approach for improved outcomes.

Language: Английский

Citations

34
Glioblastoma vaccines: past, present, and opportunities DOI Creative Commons
Zujian Xiong, Itay Raphael, Michael R. Olin

et al.

EBioMedicine, Journal Year: 2024, Volume and Issue: 100, P. 104963 - 104963

Published: Jan. 5, 2024

Glioblastoma (GBM) is one of the most lethal central nervous systems (CNS) tumours in adults. As supplements to standard care (SOC), various immunotherapies improve therapeutic effect other cancers. Among them, tumour vaccines can serve as complementary monotherapy or boost clinical efficacy with immunotherapies, such immune checkpoint blockade (ICB) and chimeric antigen receptor T cells (CAR-T) therapy. Previous studies GBM have suggested that few neoantigens could be targeted due low mutation burden, single-peptide vaccination had limited control monotherapy. Combining diverse antigens, including neoantigens, tumour-associated antigens (TAAs), pathogen-derived optimizing vaccine design strategy may help improvement. In this review, we discussed current platforms, evaluated potential antigenic targets, challenges, perspective opportunities for

Language: Английский

Citations

29
Integrated proteogenomic characterization of glioblastoma evolution DOI
Kyung‐Hee Kim, Simona Migliozzi, Harim Koo

et al.

Cancer Cell, Journal Year: 2024, Volume and Issue: 42(3), P. 358 - 377.e8

Published: Jan. 11, 2024

Language: Английский

Citations

28