Multiplatform genomic profiling and magnetic resonance imaging identify mechanisms underlying intratumor heterogeneity in meningioma

Stephen T. Magill(University of California, San Francisco), Harish N. Vasudevan(University of California, San Francisco), Kyounghee Seo(University of California, San Francisco), Javier Villanueva-Meyer(University of California, San Francisco), Abrar Choudhury(University of California, San Francisco), Siyuan Liu(University of California, San Francisco), Melike Pekmezci(University of California, San Francisco), Sarah Findakly(University of California, San Francisco), Stephanie Hilz(University of California, San Francisco), Sydney Lastella(University of California, San Francisco), Benjamin Demaree(QB3), Steve Braunstein(University of California, San Francisco), Nancy Ann Oberheim Bush(University of California, San Francisco), Manish K. Aghi(University of California, San Francisco), Philip V. Theodosopoulos(University of California, San Francisco), Penny K. Sneed(University of California, San Francisco), Adam R. Abate(QB3), Mitchel S. Berger(University of California, San Francisco), Michael McDermott(University of California, San Francisco), Daniel A. Lim(University of California, San Francisco), Erik M. Ullian(University of California, San Francisco), J Costello(University of California, San Francisco), David R. Raleigh(University of California, San Francisco)
Nature Communications
September 23, 2020
10.1038/s41467-020-18582-7
Cited by 127Open Access
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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.

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