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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\u20135 can form a complex, known as the \u2018Ragulator\u2019 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.<\/jats:p>","DOI":"10.1093\/brain\/awz370","type":"journal-article","created":{"date-parts":[[2019,11,26]],"date-time":"2019-11-26T12:11:29Z","timestamp":1574770289000},"page":"131-149","source":"Crossref","is-referenced-by-count":34,"title":["The coding and non-coding transcriptional landscape of subependymal giant cell astrocytomas"],"prefix":"10.1093","volume":"143","author":[{"given":"Anika","family":"Bongaarts","sequence":"first","affiliation":[{"name":"Department of (Neuro)Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jackelien","family":"van Scheppingen","sequence":"additional","affiliation":[{"name":"Department of (Neuro)Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam, The 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Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wim G M","family":"Spliet","sequence":"additional","affiliation":[{"name":"Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wilfred F A","family":"den Dunnen","sequence":"additional","affiliation":[{"name":"Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria E","family":"Gruber","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Medical University of Vienna, Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theresa","family":"Scholl","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Medical University of Vienna, Vienna, 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Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergiusz","family":"Jozwiak","sequence":"additional","affiliation":[{"name":"Department of Neurology and Epileptology, Children's Memorial Health Institute, Warsaw, Poland"},{"name":"Department of Child Neurology, Medical University of Warsaw, Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wieslawa","family":"Grajkowska","sequence":"additional","affiliation":[{"name":"Department of Pathology, Children's Memorial Health Institute, Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Maria","family":"Buccoliero","sequence":"additional","affiliation":[{"name":"Pathology Unit, Anna Meyer Children's Hospital, Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Caporalini","sequence":"additional","affiliation":[{"name":"Pathology Unit, Anna Meyer Children's Hospital, Florence, 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