bims-malgli 2025-06-22 papers

Nat Commun. 2025 Jun 13. 16(1): 5290

Resolving spatial subclonal genomic heterogeneity of loss of heterozygosity and extrachromosomal DNA in gliomas.

Michelle G Webb, Frances Chow, Carmel G McCullough, Bohan Zhang, John J Y Lee, Rania Bassiouni, Norman E Garrett, Kyle Hurth, John D Carpten, Gabriel Zada, David W Craig.

Mapping the spatial organization of DNA-level somatic copy number changes in tumors can provide insight to understanding higher-level molecular and cellular processes that drive pathogenesis. We describe an integrated framework of spatial transcriptomics, tumor/normal DNA sequencing, and bulk RNA sequencing to identify shared and distinct characteristics of an initial cohort of eleven gliomas of varied pathology and a replication cohort of six high-grade glioblastomas. We identify focally amplified extrachromosomal DNA (ecDNA) in four of the eleven initial gliomas, with subclonal tumor heterogeneity in two EGFR-amplified grade IV glioblastomas. In a TP53-mutated glioblastoma, we detect a subclone with EGFR amplification on ecDNA coupled to chromosome 17 loss of heterozygosity. To validate subclonal somatic aneuploidy and copy number alterations associated with ecDNA double minutes, we examine the replication cohort, identifying MDM2/MDM4 ecDNA subclones in two glioblastomas. The spatial heterogeneity of EGFR and p53 inactivation underscores the role of ecDNA in enabling rapid oncogene amplification and enhancing tumor adaptability under selective pressure.

DOI: https://doi.org/10.1038/s41467-025-59805-z

Neuro Oncol. 2025 Jun 16. pii: noaf145. [Epub ahead of print]

Glioportal: a comprehensive transcriptomic resource unveiling ligand-mediated mesenchymal transition in glioblastoma.

BACKGROUND: Multi-omics profiling of glioblastoma (GBM) has unravelled two aspects fundamental to its aggressiveness and lethality that is molecular heterogeneity inherent to the tumour and cellular plasticity modulated by microenvironment. Yet, empirical validation to identify causal factors for these complex mechanisms is rather scarce. Here, we report our endeavour in establishing Glioportal, a GBM tumour biobank with derivative preclinical models and molecular information that we leverage for basic and translational research on precision therapies.
METHODS: Bulk transcriptome and single-cell-based deconvolution analyses highlighted key features of distinct GBM subtypes and ligand-receptor pairs predicted to regulate malignant cell states plasticity. Synthetic genetic tracing tool and target genes/proteins expression analyses validated ligands-induced mesenchymal transition. This was further corroborated with phenotypic invasion/migration assays and cell-based assays using inhibitors, functional antibodies and gene silencing approaches. Proof-of-concept animal experiment was conducted using orthotopic xenograft carrying gene knockdown. Clinical relevance was assessed through immunohistochemical assay.
RESULTS: Our transcriptomic analysis highlights the integral roles of STAT3 and NF-κB pathways in maintaining intrinsic mesenchymal identity and enabling myeloid-induced plasticity towards mesenchymal phenotype. One critical ligand, TNF, confers mesenchymal adaptation and cellular invasiveness that is mitigated by TNFRSF1A, but not TNFRSF1B, loss of function. TNFRSF1A silencing significantly improves survival in vivo.
CONCLUSION: Glioportal makes a valuable resource for identifying therapeutic vulnerabilities in molecularly stratified GBM. Here, we underscore GBM dependency on myeloid-derived ligands to acquire mesenchymal traits that has clinical implications in therapeutic response and recurrence. Such reliance warrants treatment strategies targeting ligand-receptor pairs to mitigate interactions with tumour ecosystem.

Keywords: Glioblastoma tumour resource; cellular plasticity; ligand-receptor interaction; mesenchymal transition; tumour necrosis factor

DOI: https://doi.org/10.1093/neuonc/noaf145

Sci Transl Med. 2025 Jun 18. 17(803): eadr4058

Adoptive cell therapy with macrophage-drug conjugates facilitates cytotoxic drug transfer and immune activation in glioblastoma models.

The treatment of solid tumors faces substantial hurdles because of inadequate drug delivery and the immunosuppressive tumor microenvironment. To address these challenges, we developed a therapeutic platform using macrophages loaded with ferritin-drug conjugates, referred to as macrophage-drug conjugates (MDC), and applied it to glioblastoma, an immunologically cold solid tumor. MDC loaded with ferritin-conjugated monomethyl auristatin E enabled efficient, cell contact-dependent transfer of the payload by a mechanism involving transfer of iron-binding proteins, from either mouse or human macrophages preferentially into glioma cells. This targeted delivery and therapeutic efficacy was demonstrated across in vitro coculture systems, ex vivo assays using dissociated glioblastoma patient tumor samples, and in vivo using orthotopic glioblastoma mouse models, all while maintaining a favorable preclinical safety profile evidenced by minimal systemic toxicity and localized drug biodistribution. Beyond direct tumor cell killing leading to significant tumor regression and prolonged survival in these models, MDC therapy reprogrammed the immunosuppressive tumor microenvironment. Immune profiling by spectral flow cytometry revealed enhanced infiltration and activation of cytotoxic T lymphocytes and B lymphocytes while reducing immunosuppressive regulatory T cells. This culminated in a robust, durable, T cell-dependent antitumor immune response, the necessity of which was confirmed through studies in immunodeficient mouse models and by lymphocyte depletion, and which conferred protection against tumor rechallenge. The combined cytotoxic and immunomodulatory effects highlight the potential of MDC therapy as a promising strategy for glioblastoma treatment and support its further clinical development.

DOI: https://doi.org/10.1126/scitranslmed.adr4058

Cell. 2025 Jun 17. pii: S0092-8674(25)00618-X. [Epub ahead of print]

Cholinergic neuronal activity promotes diffuse midline glioma growth through muscarinic signaling.

Glutamatergic neuronal activity promotes proliferation of both oligodendrocyte precursor cells (OPCs) and gliomas, including diffuse midline glioma (DMG). However, the role of neuromodulatory brainstem neurons projecting to midline structures where DMGs arise remains unexplored. Here, we demonstrate that midbrain cholinergic neuronal activity modulates OPC and DMG proliferation in a circuit-dependent manner. Optogenetic stimulation of the cholinergic pedunculopontine nucleus (PPN) promotes glioma growth in pons, while stimulation of the laterodorsal tegmentum nucleus (LDT) drives proliferation in thalamus. DMG-bearing mice exhibit higher acetylcholine release and increased cholinergic neuronal activity over the disease course. In co-culture, cholinergic neurons enhance DMG proliferation, and acetylcholine directly acts on DMG cells. Single-cell RNA sequencing revealed high CHRM1 and CHRM3 expression in primary DMG samples. Pharmacological or genetic blockade of M1/M3 receptors abolished cholinergic activity-driven DMG proliferation. Taken together, these findings demonstrate that midbrain cholinergic long-range projections promote activity-dependent DMG growth, mirroring a parallel proliferative effect on healthy OPCs.

Keywords: DMG; LDT; OPC; PPN; cholinergic neuron; diffuse midline glioma; glioma; laterodorsal tegmentum nucleus; neuron; neuron-glioma; neuronal activity; oligodendrocyte; oligodendrogenesis; pedunculopontine nucleus

DOI: https://doi.org/10.1016/j.cell.2025.05.031