Abstract
Meningiomas are the most common primary intracranial tumors, but the molecular drivers of meningioma tumorigenesis are poorly understood. We hypothesized that investigating intratumor heterogeneity in meningiomas would elucidate biologic drivers and reveal new targets for molecular therapy. To test this hypothesis, here we perform multiplatform molecular profiling of 86 spatially-distinct samples from 13 human meningiomas. Our data reveal that regional alterations in chromosome structure underlie clonal transcriptomic, epigenomic, and histopathologic signatures in meningioma. Stereotactic co-registration of sample coordinates to preoperative magnetic resonance images further suggest that high apparent diffusion coefficient (ADC) distinguishes meningioma regions with proliferating cells enriched for developmental gene expression programs. To understand the function of these genes in meningioma, we develop a human cerebral organoid model of meningioma and validate the high ADC marker genes CDH2 and PTPRZ1 as potential targets for meningioma therapy using live imaging, single cell RNA sequencing, CRISPR interference, and pharmacology.
Highlights
Meningiomas are the most common primary intracranial tumors, but the molecular drivers of meningioma tumorigenesis are poorly understood
We found that M10G cells, which were derived from a World Health Organization (WHO) grade I meningioma, formed tumor spheres at the surface of cerebral organoids (Fig. 5c and Supplementary Movie 1)
Consistent with results using M10G cells, we found that ADH-1 blocked the proliferation (Fig. 6h) and tumorigenesis (Fig. 6i) of all primary meningioma cells tested in monocultures and in cocultures with human cerebral organoids, respectively
Summary
Meningiomas are the most common primary intracranial tumors, but the molecular drivers of meningioma tumorigenesis are poorly understood. We hypothesized that investigating intratumor heterogeneity in meningiomas would elucidate biologic drivers and reveal new targets for molecular therapy To test this hypothesis, here we perform multiplatform molecular profiling of 86 spatially-distinct samples from 13 human meningiomas. High grade meningiomas are characterized by genomic instability[12,19], suggesting that regional alterations in chromosome structure may underlie treatment resistance In support of this hypothesis, regional differences in genomic architecture[30,31,32], cell proliferation, and the frequency of somatic variants[33,34] exist in individual meningiomas. To understand the molecular mechanisms driving these differences, we stereotactically collected 86 spatially distinct samples from 13 human meningiomas, and analyzed intratumor heterogeneity using RNA sequencing, DNA methylation profiling, copy number variant (CNV) identification, tumor phylogeny generation, quantitative magnetic resonance (MR) imaging, and histopathology. Histopathologic and radiologic findings with our human cerebral organoid model of meningioma, we identify
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