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<p>Glioblastoma (GB) hijacks neuronal circuits to promote tumor progression, but the earliest neuronal responses remain poorly defined. We developed a dual-interface human iPSC-derived neuronal model to study acute paracrine signaling triggered by GB cells from two sources: serum-adapted U-87MG and serum-free NU-757. Within 24&#xa0;h, exposed neurons displayed synaptic remodeling and activation of GB-related signaling cascades. Neurons exposed to U-87MG showed decreased dendritic spine number alongside increased total ERK and phospho-p38α at spines (1). In the soma, total ERK accumulated in the nucleus while phospho-ERK was primarily cytoplasmic; nuclear p38 and cytoplasmic MLK2 also increased (2). Conversely, NU-757 exposure enhanced spine growth but reduced postsynaptic density, NMDAR, and synaptophysin levels (3). Both total and phospho-ERK showed increased nuclear localization with NU-757, while total MLK2 and p38α levels remained stable but exhibited elevated nuclear (4) and spine localization. Pharmacological MEK/ERK inhibition reduced U-87MG proliferation and migration and restored neuronal spine numbers. This model system reveals source-dependent, compartment-specific signaling dynamics that govern synaptic vulnerability and provides a platform for investigating GB initiation, recurrence, and progression, as well as therapies targeting tumor growth and neural circuit remodeling.</p> Graphical abstract <p></p>

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Dissecting acute neuronal responses to glioblastoma using a dual-interface human iPSC neuronal culture platform

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月16日

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  • Ouada Nebie,
  • Niyi Adelakun,
  • Brian Fries,
  • Luke Kollin,
  • Liwen Zhang,
  • Akhil Medikonda,
  • Monica Venere,
  • Pierre Giglio,
  • Nam Chu,
  • Nhat Le

摘要

Glioblastoma (GB) hijacks neuronal circuits to promote tumor progression, but the earliest neuronal responses remain poorly defined. We developed a dual-interface human iPSC-derived neuronal model to study acute paracrine signaling triggered by GB cells from two sources: serum-adapted U-87MG and serum-free NU-757. Within 24 h, exposed neurons displayed synaptic remodeling and activation of GB-related signaling cascades. Neurons exposed to U-87MG showed decreased dendritic spine number alongside increased total ERK and phospho-p38α at spines (1). In the soma, total ERK accumulated in the nucleus while phospho-ERK was primarily cytoplasmic; nuclear p38 and cytoplasmic MLK2 also increased (2). Conversely, NU-757 exposure enhanced spine growth but reduced postsynaptic density, NMDAR, and synaptophysin levels (3). Both total and phospho-ERK showed increased nuclear localization with NU-757, while total MLK2 and p38α levels remained stable but exhibited elevated nuclear (4) and spine localization. Pharmacological MEK/ERK inhibition reduced U-87MG proliferation and migration and restored neuronal spine numbers. This model system reveals source-dependent, compartment-specific signaling dynamics that govern synaptic vulnerability and provides a platform for investigating GB initiation, recurrence, and progression, as well as therapies targeting tumor growth and neural circuit remodeling.

Graphical abstract