Flash Assembloids: A Rapid Biofabrication of a Platform for Modeling Early Glioblastoma Invasion at the Glioblastoma-Brain Organoid Interfaces

초록

Glioblastoma (GBM) remains one of the most aggressive brain malignancies, characterized by rapid infiltration, therapeutic resistance, and dismal prognosis. Modeling GBM invasion in physiologically relevant systems has been hindered by the lack of reproducible platforms. Here, we present a bioengineered assembloid (ASM) system that integrates GBM cells encapsulated in self-degradable 5% oxidized alginate microgel (5OA) with dorsal forebrain organoids (DOs) to recapitulate early tumor-host interactions during glioblastoma invasion toward the brain. Live-cell imaging revealed GBM self-aggregation, leading to increased recruitment and invasion at the DO boundary, accompanied by strong cell-cell adhesion, nuclear compaction, and the infiltration fronts enriched in SOX2+/Vimentin+ tumor populations. Transcriptomic profiling demonstrated upregulation of adhesion, integrin clustering, and mechanosensing-associated genes, alongside downregulation of neuronal differentiation pathways, indicating a dual invasion and host suppression strategy. Comparative analyses of GBM-only constructs and DO-GBM ASMs revealed elevated expression of laminin subunits and enrichment of invasion-associated pathways, including PI3K-AKT-mTOR and TGF-beta signaling, reflecting a shift toward an invasive state at the transcriptomic level. In vivo implantation of ASMs confirmed aggressive GBM infiltration and niche remodeling, highlighting the translational relevance. These findings suggest that it recapitulates the structural, molecular, and functional hallmarks of GBM invasion and tumor-driven remodeling of the host brain microenvironment.

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