Meningioma細胞の再プログラミングと微小環境相互作用が脳浸潤の基盤となる
Ayush Aggarwal1,2,3, Mark W Youngblood4, Thiebaud Picart1,5
1Department of Neurological Surgery, University of California San Francisco, San Francisco, CA.
Background:
Meningioma brain invasion encumbers surgical resection and increases the risk of tumor recurrence, but the molecular mechanisms underlying this process are poorly understood.
Methods:
To identify molecular and cellular features of brain-invasive meningiomas, we (1) analyzed bulk RNA sequencing data from 199 meningiomas, including 33 brain-invasive tumors, (2) analyzed patient-matched single-cell RNA sequencing data of spatially mapped meningioma samples from the tumor core or brain-tumor interface (BTI), and (3) performed spatial transcriptomic sequencing of brain-invasive meningioma samples. Multiplexed immunofluorescence (IF) was used to validate bioinformatic spatial expression patterns. Functional interactions between meningioma cells and neurons were studied in meningioma/neuron co-cultures using confocal microscopy, multi-electrode array recordings, and live cell calcium imaging.
Results:
Transcriptomic analyses showed conserved enrichment of TGM2, S100A11, ZYX, and PDGFRA at the BTI across bulk, single-cell, and spatial RNA sequencing datasets. The expression of these genes at the BTI was confirmed using multiplexed IF, and single-cell bioinformatic and microscopy analyses further demonstrated enrichment of macrophages at the BTI. Co-culture assays showed neuronal hyperexcitability and increased proliferation of meningioma cells, suggesting functional communication between meningioma cells and the tumor microenvironment may contribute to meningioma growth in cases with brain invasion.
Conclusions:
Meningioma brain invasion is defined by molecular remodeling of tumor cells and functional interactions within the tumor microenvironment.
