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

in Nature cancer by 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

TLDR

  • Researchers used a murine model to study GBM invasion and tumor-associated microglia and macrophage interactions, identifying key players and mechanisms involved in invasion.
  • The study reveals that microglia play a crucial role in guiding collective tumor migration and that plexin-B2 in TAMs is critical for resolution of cell collision and restructuring the extracellular matrix.
  • These findings suggest potential therapeutic targets for GBM treatment and highlight the importance of understanding niche-specific TAM mobilization in GBM invasion.

Abstract

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.

Overview

  • The study focuses on understanding the mechanisms of Glioblastoma (GBM) invasion and the interactions between tumor cells and tumor-associated microglia and macrophages (TAMs).
  • The researchers used an immunocompetent murine model to map GBM invasion and TAM interactions, and analyzed the gene expression profiles of tumor cells and TAMs using single-cell RNA sequencing.
  • The primary objective of the study is to identify the key players and mechanisms involved in GBM invasion and resistance to therapies, and to explore potential strategies to target GBM invasion.

Comparative Analysis & Findings

  • The study demonstrates that microglia are mobilized ahead of invasion, transforming morphologically and functionally to form 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, indicating the conservation of these mechanisms across species.

Implications and Future Directions

  • The study highlights the critical role of plexin-B2 in TAMs for resolving cell collision, aligning GBM cells and restructuring the extracellular matrix.
  • Ablating plexin-B2 in TAMs disrupted invasion tracks, shifting GBM growth from infiltrative to bulk expansion, providing a potential therapeutic target.
  • The findings suggest that understanding niche-specific TAM mobilization and anatomical-functional invasion units could open new strategies to target GBM invasion, potentially improving treatment outcomes.
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