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Researchers used CRISPR-Cas9 screening in pediatric brain tumor models to identify biological factors that control how cancer cells take up therapeutic nanoparticles. They discovered that beta-catenin (CTNNB1) acts as a negative regulator of nanoparticle uptake, and that depleting this protein changes cell membrane properties and shifts cells from bulk fluid uptake to receptor-mediated uptake. The study also found that MAPK and mTOR signaling pathways modulate nanoparticle delivery, with genetic and drug-based interventions producing similar effects.
Why it matters
This research could improve targeted drug delivery to diffuse midline gliomas, aggressive pediatric brain tumors with poor prognosis. By identifying biological pathways that control nanoparticle uptake, the findings may enable strategies to enhance therapeutic delivery to these hard-to-treat tumors through genetic or pharmacological manipulation of cellular uptake mechanisms.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
Nanoparticle drug delivery systems hold considerable promise for locoregional administration to central nervous system tumors, yet the biological determinants of nanoparticle-cancer cell interactions remain poorly understood. Using patient-derived histone-mutant diffuse midline glioma (DMG) models, we performed a pooled CRISPR-Cas9 perturbation screen to systematically identify regulators of liposomal nanoparticle delivery. The screen identified candidate genes spanning endocytosis, vesicle transport, and metabolic signaling, revealing that nanoparticle delivery is governed by a broader landscape than previously appreciated. Among these, CTNNB1, or {beta}-catenin, emerged as a common negative regulator across two independent DMG models and two distinct nanoparticle surface chemistries. Transcriptomic profiling of CTNNB1-depleted DMG cells revealed upregulation of membrane remodeling and extracellular matrix gene programs, accompanied by reduced cell stiffness measured by a microfluidic acoustic scattering assay. This resulted in a shift in endocytic activity characterized by decreased bulk-phase macropinocytosis and increased receptor-mediated endocytosis. We further identified MAPK and mTOR pathway members as nanoparticle trafficking modulators, and demonstrated concordance between genetic and pharmacologic perturbations in modulating the liposomal nanoparticle interactions in pediatric DMG cells. These findings establish a biology-first screening approach for identifying previously unappreciated regulators with potential relevance to nanoparticle-based therapeutic strategies in pediatric brain tumors.
Source: Phenotypic screens identify biologic regulators of nanoparticle uptake in diffuse midline glioma