The Meningioma Enhancer Landscape Delineates Novel Subgroups and Drives Druggable Dependencies.
The Meningioma Enhancer Landscape Delineates Novel Subgroups and Drives Druggable Dependencies.
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DOI：
10.1158/2159-8290.cd-20-0160
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发表时间：
2020-11
期刊：
影响因子：
28.2
通讯作者：
Rich JN
中科院分区：
文献类型：
--
作者：
Prager BC;Vasudevan HN;Dixit D;Bernatchez JA;Wu Q;Wallace LC;Bhargava S;Lee D;King BH;Morton AR;Gimple RC;Pekmezci M;Zhu Z;Siqueira-Neto JL;Wang X;Xie Q;Chen C;Barnett GH;Vogelbaum MA;Mack SC;Chavez L;Perry A;Raleigh DR;Rich JN
脑膜瘤是最常见的原发性颅内肿瘤，目前的分类提供的治疗指导有限。在这里，我们研究了 33 个肿瘤的脑膜瘤增强子景观，根据预后对患者进行分层，并确定新的脑膜瘤特异性依赖性。增强剂将脑膜瘤有力地分为三个生物学上不同的组（脂肪生成/胆固醇、中胚层和神经嵴），通过不同的激素谱系转录调节因子来区分。脑膜瘤景观聚集了内在脑肿瘤和激素反应性系统性癌症，脑膜瘤亚组反映了黄体酮或雄激素激素信号传导。增强分类识别出预后不良的肿瘤子集，无论组织学分级如何。超级增强子特征预测药物依赖性，其体外疗效优于基于 NF2 基因组图谱的治疗。 DUSP1（一种新型可药物化脑膜瘤靶标）的抑制会损害体内肿瘤生长。总的来说，表观遗传景观有助于脑膜瘤分类和新疗法的识别。
Meningiomas are the most common primary intracranial tumor with current classification offering limited therapeutic guidance. Here, we interrogated meningioma enhancer landscapes from 33 tumors to stratify patients based upon prognosis and identify novel meningioma-specific dependencies. Enhancers robustly stratified meningiomas into three biologically distinct groups (adipogenesis/cholesterol, mesodermal and neural crest) distinguished by distinct hormonal lineage transcriptional regulators. Meningioma landscapes clustered with intrinsic brain tumors and hormonally-responsive systemic cancers with meningioma subgroups reflecting progesterone or androgen hormonal signaling. Enhancer classification identified a subset of tumors with poor prognosis, irrespective of histological grading. Super enhancer signatures predicted drug dependencies with superior in vitro efficacy to treatment based upon the NF2 genomic profile. Inhibition of DUSP1, a novel and druggable meningioma target, impaired tumor growth in vivo. Collectively, epigenetic landscapes empower meningioma classification and identification of novel therapies.