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<p>Glioblastoma (GBM) lethality stems from uncontrolled growth and infiltration. Using an immunocompetent murine model, we mapped GBM invasion and tumor-associated microglia and macrophage (TAM) interactions. We show that microglia are mobilized ahead of invasion, transforming morphologically and functionally—first forming glial nets around tumor infiltrates and then organizing into ‘oncostreams’ guiding collective migration. Single-cell RNA sequencing revealed three distinct states for tumor cells and microglia, corresponding to invasive niches versus tumor bulk. The invasive patterns and niche-specific gene signatures of tumor cells and TAMs were validated in human GBMs. We further identified a critical role of plexin-B2 in TAMs for resolving cell collision, aligning GBM cells and restructuring the extracellular matrix. Plexin-B2 ablation in TAMs disrupted invasion tracks, shifting GBM growth from infiltrative to bulk expansion. Understanding niche-specific TAM mobilization and anatomical–functional invasion units opens new strategies to target GBM invasion.</p>

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Glioblastoma shift from bulk to infiltrative growth is guided by plexin-B2-mediated microglia alignment in invasive niches

  • 期刊论文

  • 发表日期：

    2025年5月29日

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  • Sangjo Kang,
  • Mary E. Ughetta,
  • Jack Y. Zhang,
  • Valerie J. Marallano,
  • Anirudh Sattiraju,
  • Theodore Hannah,
  • Shalaka Wahane,
  • Aarthi Ramakrishnan,
  • Molly Estill,
  • Nadejda M. Tsankova,
  • Li Shen,
  • Alexander M. Tsankov,
  • Roland H. Friedel,
  • Hongyan Zou

摘要

Glioblastoma (GBM) lethality stems from uncontrolled growth and infiltration. Using an immunocompetent murine model, we mapped GBM invasion and tumor-associated microglia and macrophage (TAM) interactions. We show that microglia are mobilized ahead of invasion, transforming morphologically and functionally—first forming glial nets around tumor infiltrates and then organizing into ‘oncostreams’ guiding collective migration. Single-cell RNA sequencing revealed three distinct states for tumor cells and microglia, corresponding to invasive niches versus tumor bulk. The invasive patterns and niche-specific gene signatures of tumor cells and TAMs were validated in human GBMs. We further identified a critical role of plexin-B2 in TAMs for resolving cell collision, aligning GBM cells and restructuring the extracellular matrix. Plexin-B2 ablation in TAMs disrupted invasion tracks, shifting GBM growth from infiltrative to bulk expansion. Understanding niche-specific TAM mobilization and anatomical–functional invasion units opens new strategies to target GBM invasion.