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<p>Glioblastoma (GBM) remains one of the most aggressive human cancers, driven by cellular plasticity and dynamic interactions with the neurovascular niche. Yet, further refinement of existing preclinical models is needed to improve the reproduction of the human brain–vascular interface and facilitate the study of tumor-host crosstalk and invasion. To address this limitation, we developed a human induced pluripotent stem cell (hiPSC)-derived cortico-endothelial (CO + EO) assembloid model by fusing cortical and endothelial organoids. These assembloids spontaneously form branched vascular networks enriched in tight junction proteins (CLDN5, OCLN, ZO-1), thereby recapitulating key BBB-like features and providing a physiologically relevant human platform to investigate GBM–neurovascular interactions. Using this system, we uncovered a previously unrecognized CELF2-dependent glioma stem cell (GSC) tropism. CELF2-expressing GSCs preferentially infiltrate neural regions, where they induce neuronal apoptosis and disrupt endothelial tight junction structure, supporting an aggressive phenotype. In contrast, CELF2-deficient GSCs lose neurotropism, acquire mesenchymal features, and are redirected toward vascular compartments. This endothelial affinity depends on the scaffold protein AHNAK, strongly expressed at the plasma membrane of CELF2-deficient cells and enriched at tumor-endothelial interfaces. AHNAK knockdown partially abolishes endothelial infiltration, demonstrating its role in GBM vascular tropism. Moreover, analysis of patient GBM specimens confirmed that CELF2-positive tumor cells are enriched in poorly vascularized, mitotically active regions and are largely excluded from vessel-rich zones, closely resembling the behavior observed in assembloids. Transcriptomic profiling further revealed that CELF2 promotes a neuronal progenitor-like program while repressing mesenchymal and vascular-associated gene signatures, thereby shaping tumor identity, invasive behavior, and tissue preference. Collectively, this study establishes CO + EO assembloids as an original human model of GBM plasticity at the neurovascular interface. We identify CELF2 as a master regulator of GSC tropism and AHNAK as a mediator of vascular affinity, revealing a molecular axis that governs GBM invasion and providing potential avenues for future therapeutic intervention.</p><p></p>

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Human cortico-vascular assembloids reveal a CELF2-AHNAK-dependent switch from neuronal to endothelial tropism in glioblastoma cells

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年8月5日

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  • Michele Bertacchi,
  • Annie Ladoux,
  • Alexa Saliou,
  • Gwendoline Maharaux,
  • Clément Peux,
  • Laurent Turchi,
  • Béatrice Polo,
  • Hervé Chneiweiss,
  • Elias El-Habr,
  • Marie Pierre Junier,
  • Fabien Almairac,
  • Fanny Burel-Vandenbos,
  • Michèle Studer,
  • Thierry Virolle

摘要

Glioblastoma (GBM) remains one of the most aggressive human cancers, driven by cellular plasticity and dynamic interactions with the neurovascular niche. Yet, further refinement of existing preclinical models is needed to improve the reproduction of the human brain–vascular interface and facilitate the study of tumor-host crosstalk and invasion. To address this limitation, we developed a human induced pluripotent stem cell (hiPSC)-derived cortico-endothelial (CO + EO) assembloid model by fusing cortical and endothelial organoids. These assembloids spontaneously form branched vascular networks enriched in tight junction proteins (CLDN5, OCLN, ZO-1), thereby recapitulating key BBB-like features and providing a physiologically relevant human platform to investigate GBM–neurovascular interactions. Using this system, we uncovered a previously unrecognized CELF2-dependent glioma stem cell (GSC) tropism. CELF2-expressing GSCs preferentially infiltrate neural regions, where they induce neuronal apoptosis and disrupt endothelial tight junction structure, supporting an aggressive phenotype. In contrast, CELF2-deficient GSCs lose neurotropism, acquire mesenchymal features, and are redirected toward vascular compartments. This endothelial affinity depends on the scaffold protein AHNAK, strongly expressed at the plasma membrane of CELF2-deficient cells and enriched at tumor-endothelial interfaces. AHNAK knockdown partially abolishes endothelial infiltration, demonstrating its role in GBM vascular tropism. Moreover, analysis of patient GBM specimens confirmed that CELF2-positive tumor cells are enriched in poorly vascularized, mitotically active regions and are largely excluded from vessel-rich zones, closely resembling the behavior observed in assembloids. Transcriptomic profiling further revealed that CELF2 promotes a neuronal progenitor-like program while repressing mesenchymal and vascular-associated gene signatures, thereby shaping tumor identity, invasive behavior, and tissue preference. Collectively, this study establishes CO + EO assembloids as an original human model of GBM plasticity at the neurovascular interface. We identify CELF2 as a master regulator of GSC tropism and AHNAK as a mediator of vascular affinity, revealing a molecular axis that governs GBM invasion and providing potential avenues for future therapeutic intervention.