{ "abstract": "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. Schematic representation of CO + EO assembloids comprising an endothelial (yellow) and a cortical (red) domain. On the left, control CELF2-expressing GBM cells preferentially infiltrate the neuronal compartment, where they trigger neuronal apoptosis and disrupt the expression of the tight junction protein CLDN5 upon contact with endothelial cells. On the right, CELF2-deprived GBM cells exhibit reduced neural invasion and increased tropism for endothelial cells, consistent with a mesenchymal signature shift partially driven by elevated AHNAK expression. These cells exert limited impact on neuronal viability and BBB integrity, and display partial loss of GSC identity, as indicated by reduced OLIG2 expression. The CO + EO assembloid model thus recapitulates key features of cortico-endothelial human tissue heterogeneity and provides a reliable platform to dissect the molecular mechanisms underlying GSC tropism and their tissue-specific interactions.", "abstract_shown": true, "affiliations": [ "Université Côte D'Azur, CNRS, Inserm, iBV, Nice, France.", "DRCI, CHU de Nice, Nice, France.", "Sorbonne Université, CNRS, INSERM, Institut de Biologie Paris Seine, Center for Neuroscience at Sorbonne Université, 7 Quai Saint-Bernard, Paris, France.", "Service de Neurochirurgie, Hôpital Pasteur, CHU de Nice, Nice, France.", "Service d'Anatomopathologie, Hôpital Pasteur, CHU de Nice, Nice, France.", "Université Côte D'Azur, CNRS, Inserm, iBV, Nice, France. michele.studer@univ-cotedazur.fr.", "Université Côte D'Azur, CNRS, Inserm, iBV, Nice, France. thierry.virolle@univ-cotedazur.fr." ], "article_type": "research article", "arxiv": null, "author_total": 14, "authors": [ { "affs": [ 0 ], "name": "Michele Bertacchi", "orcid": "0000-0002-4402-4974" }, { "affs": [ 0 ], "name": "Annie Ladoux", "orcid": "0000-0003-3857-2621" }, { "affs": [ 0 ], "name": "Alexa Saliou" }, { "affs": [ 0 ], "name": "Gwendoline Maharaux" }, { "affs": [ 0 ], "name": "Clément Peux" }, { "affs": [ 0, 1 ], "name": "Laurent Turchi" }, { "affs": [ 0 ], "name": "Béatrice Polo" }, { "affs": [ 2 ], "name": "Hervé Chneiweiss", "orcid": "0000-0001-7675-5061" }, { "affs": [ 2 ], "name": "Elias El-Habr", "orcid": "0000-0002-4531-9707" }, { "affs": [ 2 ], "name": "Marie Pierre Junier", "orcid": "0000-0002-5731-0929" }, { "affs": [ 0, 3 ], "name": "Fabien Almairac" }, { "affs": [ 0, 4 ], "name": "Fanny Burel-Vandenbos" }, { "affs": [ 5 ], "name": "Michèle Studer" }, { "affs": [ 6 ], "name": "Thierry Virolle", "orcid": "0000-0003-1464-0917" } ], "bibtex": "https://research.draconitic.com/paper/ewqhgxhdh9e71.bib", "cited_by": 0, "doi": "10.1038/s41419-026-09169-z", "fulltext_url": "https://europepmc.org/articles/PMC13728187", "id": "ewqhgxhdh9e71", "issns": [ "2041-4889" ], "landing_url": "https://europepmc.org/article/MED/42971976", "language": "eng", "licence": "CC-BY", "licence_label": "CC BY", "licence_source": "article", "licence_url": "https://creativecommons.org/licenses/by/4.0/", "metadata_licence": null, "native_subjects": [ [ "heading", "Article" ], [ "openalex", "2716|Glioma Diagnosis and Treatment" ] ], "openalex": "W4415442493", "pdf_url": "https://europepmc.org/articles/PMC13728187?pdf=render", "pmcid": "PMC13728187", "pmid": "42971976", "published": "2026-08-05", "publisher": "Nature Publishing Group", "ris": "https://research.draconitic.com/paper/ewqhgxhdh9e71.ris", "sources": [ { "first_seen": "2026-11-04T15:20:45Z", "native_id": "MED:42971976", "source": "europepmc", "url": "https://europepmc.org/article/MED/42971976" }, { "first_seen": "2026-11-06T12:23:55Z", "native_id": "PMC13728187", "source": "pmc", "url": "https://doi.org/10.1038/s41419-026-09169-z" } ], "subjects": [ { "field": "medicine", "origin": "openalex:2716|Glioma Diagnosis and Treatment", "subfield": "human-genetics" } ], "title": "Human cortico-vascular assembloids reveal a CELF2-AHNAK-dependent switch from neuronal to endothelial tropism in glioblastoma cells.", "title_text": "Human cortico-vascular assembloids reveal a CELF2-AHNAK-dependent switch from neuronal to endothelial tropism in glioblastoma cells.", "type": "peer-reviewed", "updated_at": "2026-11-07T12:21:13Z", "url": "https://research.draconitic.com/paper/ewqhgxhdh9e71", "venue": "Cell death & disease", "versions": [] }