Astrocyte Identity Loss as a Driver of Glioma–Neuron Synaptic Integration

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Gliomas are highly aggressive brain tumors that not only proliferate but also integrate into neural circuits by forming functional synapses with neurons, a process that promotes tumor growth and therapy resistance. While neuron–glioma synaptic interactions have been increasingly recognized, the role of astrocytes in shaping this tumor–neural niche remains poorly understood. Astrocytes are key regulators of synapse formation in the healthy brain and are highly responsive to metabolic and disease-related stress.

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Preliminary findings from our laboratory indicate that astrocytes undergo stress-induced suppression of the identity determining factors, accompanied by activation of synaptogenic gene programs. Loss of identity determining factors in astrocytes is associated with increased expression of neuronal and synapse-related markers, suggesting a potential mechanism by which astrocytes may facilitate aberrant glioma–neuron interactions.

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In this project, we will test the hypothesis that loss of astrocytic identity determining factors promotes glioma–neuron synaptic integration. Using human iPSC-derived brain organoids containing neurons and astrocytes, we will study the identity determining factor that has been selectively suppressed in astrocytes. Glioma infiltration, tumor–neuron proximity, and synaptic marker expression will be assessed using immunofluorescence imaging and quantitative analysis. This study will provide mechanistic insight into how astrocyte identity influences brain tumor progression and may reveal new cellular targets for disrupting tumor–neural circuit integration.