Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, 94143, USA.
Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, 94143, USA.
Nat Commun. 2020 Sep 23;11(1):4803. doi: 10.1038/s41467-020-18582-7.
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.
脑膜瘤是最常见的原发性颅内肿瘤，但脑膜瘤肿瘤发生的分子驱动因素仍不清楚。我们假设研究脑膜瘤的肿瘤内异质性将阐明生物学驱动因素，并为分子治疗揭示新的靶点。为了验证这一假设，我们对 13 例人类脑膜瘤的 86 个空间上不同的样本进行了多平台分子分析。我们的数据显示，染色体结构的区域改变是脑膜瘤克隆转录组、表观基因组和组织病理学特征的基础。样本坐标的立体定向共配准到术前磁共振图像进一步表明，高表观扩散系数（ADC）可区分富含发育基因表达程序的增殖细胞的脑膜瘤区域。为了了解这些基因在脑膜瘤中的功能，我们开发了一种脑膜瘤的人类大脑类器官模型，并使用活体成像、单细胞 RNA 测序、CRISPR 干扰和药理学验证了高 ADC 标记基因 CDH2 和 PTPRZ1 作为脑膜瘤治疗的潜在靶点。
