4.7 Article

The coding and non-coding transcriptional Iandscape of subepenaymal giant cell astrocytomas

期刊

BRAIN
卷 143, 期 -, 页码 131-149

出版社

OXFORD UNIV PRESS
DOI: 10.1093/brain/awz370

关键词

SEGA; TSC; sequencing; low grade glioma

资金

  1. KIKA (Stichting Kinderen Kankervrij)
  2. Stichting AMC Foundation
  3. Stichting TSC Fonds
  4. Austrian Science Fund (FWF) [J3499]
  5. European Union 7th framework program [602531, 602391]
  6. Polish Ministerial funds for science
  7. Children's Memorial Health Institute [S132/2013]
  8. Austrian Science Fund (FWF) [J3499] Funding Source: Austrian Science Fund (FWF)

向作者/读者索取更多资源

Tuberous sclerosis complex SC; is an autosornal 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 astrocytornas (SEGAs). SEGAs may lead to impaired circulation of CSC resulting in hydrocephalus and raised inrracranial pressure in patients with TSC. Currently, surgical resection and in TORC1 inhibitors are the recommended treatment options for patients with SEGA. In the present study, high-throughput RNA-seonencim , (SEGAs n = 19, periventricular control n = 8) was used in combination with computational approaches to unravel plexity of SEGA development. We identified 9400 MRNAs and 94 microRNAs differentially in SEGAs compared to control tissue. The SEGA transcriptome profile was enriched for the mitog,en-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 LAMTOR I, LAMTOR2, LAMTOR1, 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 k 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 initia l evidence of a possible link between the constitutive activated mTORC1 pathway and a secondary driver pathway of tumour growth.

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