{
  "abstract": "Background: Glioblastoma (GBM) is an aggressive brain malignancy characterized by therapeutic resistance and frequent recurrence. Glioma-initiating cells (GICs), also known as glioma stem cells (GSCs), contribute to these features through self-renewal and resistance to genotoxic stress. Radiation therapy can paradoxically replenish the GIC compartment by inducing stem-like properties in non-stem glioma cells. We investigated whether exosomes mediate bidirectional communication that maintains the balance between GIC and non-stem populations at steady state and following irradiation. Methods: Exosomes were isolated from GIC-enriched gliomaspheres and differentiated monolayer cultures of the patient-derived GBM lines HK-374 and HK-390. Vesicles were characterized by transmission electron microscopy, nanoparticle analysis, and detection of CD63. Recipient cells were exposed to exosomes with or without 4 Gy irradiation. GIC abundance and function were evaluated using a ZsGreen-ornithine decarboxylase degron reporter, sphere-formation assays, and extreme limiting dilution analysis. Exosomal protein cargo was characterized by liquid chromatography-tandem mass spectrometry and Gene Ontology enrichment analysis. Single-cell RNA sequencing was used to evaluate changes in cellular composition upon exosome treatment. Results: Isolated vesicles displayed characteristic exosomal morphology, a mean diameter of 41.6 +/- 14.7 nm, and CD63 expression. Irradiation produced a 12-fold increase in GIC reporter-positive cells among initially reporter-negative differentiated cells. Gliomasphere-derived exosomes significantly and dose-dependently suppressed this radiation-induced phenotype conversion and reduced functional GIC frequency and self-renewal in both patient-derived lines. Conversely, exosomes from GIC-depleted monolayer cultures increased reporter-positive cells two- to three- fold and enhanced the frequency and self-renewal of existing GICs. Proteomic analysis identified 1,796 exosomal proteins, including 336 differentially abundant candidates. Gliomasphere-derived exosomes were enriched in proteins associated with translation, RNA binding, actin organization, cytoskeletal regulation, and intracellular trafficking. Monolayer-derived exosomes were enriched in extracellular-matrix and stem-cell-niche components, including NID2, LAMA5, LAMB1, LAMB2, LAMC1, THBS1, TGFBI, IQGAP3, and APOE. Single-cell transcriptomic analysis showed that gliomasphere-derived exosomes prevented the radiation-induced expansion of neural progenitor-like cells, consistent with suppression of an induced stem-like state. Treatment of gliomaspheres with monolayer-derived exosomes left their overall cellular composition largely but enriched MYC-target, E2F-target, and oxidative-phosphorylation programs, suggesting that increased sphere formation may partly reflect enhanced proliferative capacity. Conclusions: GBM cells use exosomes to establish a bidirectional feedback circuit between stem-like and differentiated tumor-cell compartments. GIC-derived exosomes constrain radiation-induced conversion of non-stem glioma cells into GICs, whereas differentiated-cell-derived exosomes promote a niche that supports GIC maintenance and self-renewal, potentially through expansion of a mixed-vascular-like population containing neurovascular progenitors. Whether exosomal IQGAP3 contributes to the expansion of this GIC population remains to be determined. These findings identify exosome-mediated intercellular communication as a potential mechanism regulating GBM cellular homeostasis, treatment resistance, and recurrence.",
  "abstract_shown": true,
  "affiliations": [
    "UCLA"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 6,
  "authors": [
    {
      "name": "L. Azizi"
    },
    {
      "name": "L. He"
    },
    {
      "name": "A. Bhaduri"
    },
    {
      "name": "L. Liau"
    },
    {
      "name": "H. I. Kornblum"
    },
    {
      "affs": [
        0
      ],
      "name": "F. Pajonk"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/7xzxctd5y5x4y.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.02.748690",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.09.02.748690v1.full",
  "id": "7xzxctd5y5x4y",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.09.02.748690v1",
  "language": null,
  "licence": "CC-BY-ND",
  "licence_label": "CC BY-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "neuroscience"
    ],
    [
      "openalex",
      "1312|Extracellular vesicles in disease"
    ]
  ],
  "openalex": "W7211971563",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.09.02.748690v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-02",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/7xzxctd5y5x4y.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:20:12Z",
      "native_id": "10.64898/2026.09.02.748690",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.09.02.748690v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:neuroscience",
      "subfield": "neuroscience"
    }
  ],
  "title": "Exosome-Mediated Bidirectional Signaling Regulates Glioma Stem-Cell Homeostasis and Radiation-Induced Plasticity",
  "title_text": "Exosome-Mediated Bidirectional Signaling Regulates Glioma Stem-Cell Homeostasis and Radiation-Induced Plasticity",
  "type": "preprint",
  "updated_at": "2026-10-30T12:20:12Z",
  "url": "https://research.draconitic.com/paper/7xzxctd5y5x4y",
  "venue": "bioRxiv",
  "versions": []
}