Enhancer landscape of meningioma

Meningiomas are the most common primary intracranial tumor. However, surgical resection and radiation frequently fail to eliminate high grade tumors, leading to significant morbidity and mortality. Predicting which tumors will recur rapidly is critical to effective treatment strategies. To address the prognostic challenges and dearth of therapeutic targets, we interrogated the enhancer landscape of a diverse cohort of meningiomas. Enhancers robustly stratified meningiomas into three biologically distinct groups and identified a subset of tumors with a poor prognosis, independent of histological grading. Integrating enhancer networks with transcriptional profiles revealed unique lineage transcriptional regulators associated with each subgroup. A strong hormonal epidemiologic association is well-characterized in meningiomas, but mechanistic insight remains lacking. We identified differential hormonal regulators that stratified between subgroups, and implicated progesterone receptor in maintaining the super enhancer network of a subset of tumors. Super enhancers marked critical and druggable dependencies across a panel of meningioma models.

脑膜瘤（Meningiomas）是最常见的原发性颅内肿瘤。然而，手术切除与放射治疗往往无法彻底清除高级别脑膜瘤，进而导致显著的发病与死亡后果。提前预判哪些肿瘤会快速复发，对于制定有效的治疗策略至关重要。为应对预后评估难题与治疗靶点匮乏的现状，本研究对一组多样化的脑膜瘤队列的增强子图谱（Enhancer Landscape）进行了系统解析。研究发现，增强子（Enhancers）可将脑膜瘤稳定地划分为三个具有独特生物学特征的亚型，并可识别出一组预后不良的肿瘤亚群，且该亚群的预后与组织学分级无关。将增强子调控网络与转录组图谱（Transcriptional Profiles）整合分析后，本研究鉴定出了与每个亚型特异性相关的独特谱系转录调控因子。脑膜瘤与激素的强流行病学关联已得到充分证实，但相关的机制阐释仍存在空白。本研究鉴定出了在各亚型间存在表达差异的激素调控因子，并证实孕激素受体（Progesterone Receptor）可维持某一肿瘤亚群的超级增强子（Super Enhancers）网络。在一组脑膜瘤模型中，超级增强子可标记出关键且可靶向治疗的疾病依赖位点。