Tuberous sclerosis complex (TSC) is an autosomal dominantly inherited neurocutaneous disorder caused by inactivating mutations in TSC1 or TSC2, key regulators of the mechanistic target of rapamycin complex 1 (mTORC1) pathway. In the CNS, TSC is characterized by cortical tubers, subependymal nodules and subependymal giant cell astrocytomas (SEGAs). SEGAs may lead to impaired circulation of CSF resulting in hydrocephalus and raised intracranial pressure in patients with TSC. Currently, surgical resection and mTORC1 inhibitors are the recommended treatment options for patients with SEGA. In the present study, high-throughput RNA-sequencing (SEGAs n = 19, periventricular control n = 8) was used in combination with computational approaches to unravel the complexity of SEGA development. We identified 9400 mRNAs and 94 microRNAs differentially expressed in SEGAs compared to control tissue. The SEGA transcriptome profile was enriched for the mitogen-activated protein kinase (MAPK) pathway, a major regulator of cell proliferation and survival. Analysis at the protein level confirmed that extracellular signal-regulated kinase (ERK) is activated in SEGAs. Subsequently, the inhibition of ERK independently of mTORC1 blockade decreased efficiently the proliferation of primary patient-derived SEGA cultures. Furthermore, we found that LAMTOR1, LAMTOR2, LAMTOR3, LAMTOR4 and LAMTOR5 were overexpressed at both gene and protein levels in SEGA compared to control tissue. Taken together LAMTOR1-5 can form a complex, known as the 'Ragulator' complex, which is known to activate both mTORC1 and MAPK/ERK pathways. Overall, this study shows that the MAPK/ERK pathway could be used as a target for treatment independent of, or in combination with mTORC1 inhibitors for TSC patients. Moreover, our study provides initial evidence of a possible link between the constitutive activated mTORC1 pathway and a secondary driver pathway of tumour growth.

中文翻译：

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室管膜下巨细胞星形细胞瘤的编码和非编码转录景观。

结节性硬化症 (TSC) 是一种常染色体显性遗传性神经皮肤疾病，由 TSC1 或 TSC2 失活突变引起，TSC1 或 TSC2 是雷帕霉素复合物 1 (mTORC1) 通路机制靶标的关键调节因子。在中枢神经系统中，TSC 的特点是皮质结节、室管膜下结节和室管膜下巨细胞星形细胞瘤 (SEGA)。SEGA 可能会导致脑脊液循环受损，导致 TSC 患者出现脑积水和颅内压升高。目前，手术切除和mTORC1抑制剂是SEGA患者的推荐治疗选择。在本研究中，高通量 RNA 测序（SEGA n = 19，脑室周围控制 n = 8）与计算方法结合使用，以揭示 SEGA 开发的复杂性。我们鉴定出 SEGA 中与对照组织相比差异表达的 9400 个 mRNA 和 94 个 microRNA。SEGA 转录组谱丰富了丝裂原激活蛋白激酶 (MAPK) 途径，这是细胞增殖和存活的主要调节因子。蛋白质水平的分析证实细胞外信号调节激酶 (ERK) 在 SEGA 中被激活。随后，独立于 mTORC1 阻断的 ERK 抑制有效地降低了原代患者来源的 SEGA 培养物的增殖。此外，我们发现与对照组织相比，SEGA 中 LAMTOR1、LAMTOR2、LAMTOR3、LAMTOR4 和 LAMTOR5 在基因和蛋白质水平上均过表达。LAMTOR1-5 结合在一起可以形成一个复合物，称为“Ragulator”复合物，已知它可以激活 mTORC1 和 MAPK/ERK 通路。总的来说，这项研究表明 MAPK/ERK 通路可以作为 TSC 患者独立于 mTORC1 抑制剂或与 mTORC1 抑制剂联合治疗的靶标。此外，我们的研究提供了初步证据，证明组成型激活的 mTORC1 通路与肿瘤生长的次要驱动通路之间可能存在联系。