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The coding and non-coding transcriptional landscape of subependymal giant cell astrocytomas

A. Bongaarts, J. van Scheppingen, A. Korotkov, C. Mijnsbergen, JJ. Anink, FE. Jansen, WGM. Spliet, WFA. den Dunnen, VE. Gruber, T. Scholl, S. Samueli, JA. Hainfellner, M. Feucht, K. Kotulska, S. Jozwiak, W. Grajkowska, AM. Buccoliero, C....

. 2020 ; 143 (1) : 131-149. [pub] 20200101

Jazyk angličtina Země Velká Británie

Typ dokumentu časopisecké články, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc20025289

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.

Center for Experimental and Molecular Medicine and Department of Clinical Epidemiology Biostatistics and Bioinformatics Amsterdam UMC University of Amsterdam Amsterdam The Netherlands

Department of Neurology and Epileptology Children's Memorial Health Institute Warsaw Poland

Department of Neurology and Epileptology Children's Memorial Health Institute Warsaw Poland Department of Child Neurology Medical University of Warsaw Warsaw Poland

Department of Neuropathology University Hospital Erlangen Erlangen Germany

Department of Neurosurgery Anna Meyer Children's Hospital Florence Italy

Department of Paediatric Neurology Charles University 2nd Faculty of Medicine Motol University Hospital Prague Czech Republic

Department of Pathology Amsterdam UMC University of Amsterdam Amsterdam The Netherlands

Department of Pathology and Medical Biology University of Groningen University Medical Center Groningen Groningen The Netherlands

Department of Pathology and Molecular Medicine Charles University 2nd Faculty of Medicine Motol University Hospital Prague Czech Republic

Department of Pathology Children's Memorial Health Institute Warsaw Poland

Department of Pathology University Medical Center Utrecht Utrecht The Netherlands

Department of Pediatric Neurology University Medical Center Utrecht Utrecht The Netherlands

Department of Pediatrics Medical University of Vienna Vienna Austria

Department of The Netherlands

Institute of Neurology Medical University of Vienna Vienna Austria

Pathology Unit Anna Meyer Children's Hospital Florence Italy

Princess Máxima Center for Pediatric Oncology Utrecht The Netherlands

Princess Máxima Center for Pediatric Oncology Utrecht The Netherlands Department of Pediatric Oncology Emma Children's Hospital Amsterdam UMC University of Amsterdam Amsterdam The Netherlands

Citace poskytuje Crossref.org

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