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首页> 外文期刊>Nature >Targeting neuronal activity-regulated neuroligin-3 dependency in high-grade glioma
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Targeting neuronal activity-regulated neuroligin-3 dependency in high-grade glioma

机译：靶向神经胶质瘤中神经元活性调节的Neuroligin-3依赖性

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摘要

High-grade gliomas (HGG) are a devastating group of cancers, and represent the leading cause of brain tumour-related death in both children and adults. Therapies aimed at mechanisms intrinsic to glioma cells have translated to only limited success; effective therapeutic strategies will need also to target elements of the tumour microenvironment that promote glioma progression. Neuronal activity promotes the growth of a range of molecularly and clinically distinct HGG types, including adult and paediatric glioblastoma (GBM), anaplastic oligodendroglioma, and diffuse intrinsic pontine glioma (DIPG)(1). An important mechanism that mediates this neural regulation of brain cancer is activity-dependent cleavage and secretion of the synaptic adhesion molecule neuroligin-3 (NLGN3), which promotes glioma proliferation through the PI3K-mTOR pathway(1). However, the necessity of NLGN3 for glioma growth, the proteolytic mechanism of NLGN3 secretion, and the further molecular consequences of NLGN3 secretion in glioma cells remain unknown. Here we show that HGG growth depends on microenvironmental NLGN3, identify signalling cascades downstream of NLGN3 binding in glioma, and determine a therapeutically targetable mechanism of secretion. Patient-derived orthotopic xenografts of paediatric GBM, DIPG and adult GBM fail to grow in Nlgn3 knockout mice. NLGN3 stimulates several oncogenic pathways, such as early focal adhesion kinase activation upstream of PI3K-mTOR, and induces transcriptional changes that include upregulation of several synapse-related genes in glioma cells. NLGN3 is cleaved from both neurons and oligodendrocyte precursor cells via the ADAM10 sheddase. ADAM10 inhibitors prevent the release of NLGN3 into the tumour microenvironment and robustly block HGG xenograft growth. This work defines a promising strategy for targeting NLGN3 secretion, which could prove transformative for HGG therapy.
机译：高度神经胶质瘤（HGG）是一组毁灭性的癌症，是儿童和成人脑瘤相关死亡的主要原因。针对神经胶质瘤细胞固有机制的疗法仅取得了有限的成功。有效的治疗策略也将需要靶向促进神经胶质瘤进展的肿瘤微环境要素。神经元活性促进了一系列分子和临床上不同的HGG类型的生长，包括成人和小儿成胶质细胞瘤（GBM），间变性少突胶质细胞瘤和弥漫性桥脑神经胶质瘤（DIPG）（1）。介导这种脑癌神经调节的重要机制是依赖于活性的分裂和突触粘附分子Neuroligin-3（NLGN3）的分泌，其通过PI3K-mTOR途径促进神经胶质瘤增殖（1）。但是，对于神经胶质瘤生长而言，NLGN3的必要性，NLGN3分泌的蛋白水解机制以及神经胶质瘤细胞中NLGN3分泌的进一步分子后果仍然未知。在这里，我们显示HGG的生长取决于微环境NLGN3，确定神经胶质瘤中NLGN3结合下游的信号级联，并确定分泌的治疗性靶向机制。小儿GBM，DIPG和成年GBM的患者源原位异种移植物在Nlgn3基因敲除小鼠中无法生长。 NLGN3刺激多种致癌途径，例如PI3K-mTOR上游的早期粘着斑激酶活化，并诱导转录变化，其中包括神经胶质瘤细胞中一些与突触相关的基因上调。 NLGN3通过ADAM10脱落酶从神经元和少突胶质细胞前体细胞中分离出来。 ADAM10抑制剂可防止NLGN3释放到肿瘤微环境中，并有力地阻止HGG异种移植物的生长。这项工作确定了针对NLGN3分泌的有前途的策略，可以证明对HGG治疗具有转化性。

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  • 来源
    《Nature》 |2017年第7673期|533-537|共5页
  • 作者

    Venkatesh Humsa S. .; Tam Lydia T. .; Woo Pamelyn J.; Lennon James; Nagaraja Surya; Gillespie Shawn M. .; Ni Jing; Duveau Damien Y.; Morris Patrick J.; Zhao Jean J.; Thomas Craig J.; Monje Michelle;

  • 作者单位

    Stanford Univ, Dept Neurol, Sch Med, Stanford, CA 94305 USA|Stanford Univ, Sch Med, Canc Biol Grad Program, Stanford, CA 94305 USA;

    Stanford Univ, Dept Neurol, Sch Med, Stanford, CA 94305 USA;

    Stanford Univ, Dept Neurol, Sch Med, Stanford, CA 94305 USA;

    Stanford Univ, Dept Neurol, Sch Med, Stanford, CA 94305 USA;

    Stanford Univ, Dept Neurol, Sch Med, Stanford, CA 94305 USA;

    Stanford Univ, Dept Neurol, Sch Med, Stanford, CA 94305 USA|Stanford Univ, Sch Med, Canc Biol Grad Program, Stanford, CA 94305 USA;

    Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA|Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA USA;

    Natl Ctr Adv Translat Sci, Div Preclin Innovat, NIH, Bldg 10, Bethesda, MD 20892 USA;

    Natl Ctr Adv Translat Sci, Div Preclin Innovat, NIH, Bldg 10, Bethesda, MD 20892 USA;

    Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA|Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA USA;

    Natl Ctr Adv Translat Sci, Div Preclin Innovat, NIH, Bldg 10, Bethesda, MD 20892 USA;

    Stanford Univ, Dept Neurol, Sch Med, Stanford, CA 94305 USA|Stanford Univ, Dept Pediat, Sch Med, Stanford, CA 94305 USA|Stanford Univ, Dept Pathol, Sch Med, Stanford, CA 94305 USA|Stanford Univ, Inst Stem Cell Biol & Regenerat Med, Stanford, CA 94305 USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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