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

Bongaarts A, Van Scheppingen J, Korotkov A, Mijnsbergen C, Anink JJ, Jansen FE, Spliet WG, Den Dunnen WF, Gruber VE, Scholl T, Samueli S, Hainfellner JA, Feucht M, Kotulska K, Jozwiak S, Grajkowska W, Buccoliero AM, Caporalini C, Giordano F, Genitori L, Coras R, Blümcke I, Krsek P, Zamecnik J, Meijer L, Scicluna BP, Schouten-Van Meeteren AY, Mühlebner A, Mills JD, Aronica E (2020)

Publication Type: Journal article

Publication year: 2020

Journal

Brain Oxford University Press

Book Volume: 143

Pages Range: 131-149

Journal Issue: 1

DOI: 10.1093/brain/awz370

Abstract

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, highthroughput 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.

Authors with CRIS profile

Ingmar Blümcke Lehrstuhl für Neuropathologie

Involved external institutions

University of Amsterdam NL Netherlands (NL) Princess Máxima Center NL Netherlands (NL) University Medical Centre Utrecht (UMC Utrecht) NL Netherlands (NL) Medizinische Universität Wien AT Austria (AT) Motol University Hospital / Fakultní nemocnice v Motole CZ Czech Republic (CZ) Children's Memorial Health Institute / Instytut "Pomnik - Centrum Zdrowia Dziecka" PL Poland (PL) Azienda Ospedaliera Universitaria Meyer IT Italy (IT) University of Groningen / Rijksuniversiteit Groningen NL Netherlands (NL)

How to cite

APA:

Bongaarts, A., Van Scheppingen, J., Korotkov, A., Mijnsbergen, C., Anink, J.J., Jansen, F.E.,... Aronica, E. (2020). The coding and non-coding transcriptional landscape of subependymal giant cell astrocytomas. Brain, 143(1), 131-149. https://doi.org/10.1093/brain/awz370

MLA:

Bongaarts, Anika, et al. "The coding and non-coding transcriptional landscape of subependymal giant cell astrocytomas." Brain 143.1 (2020): 131-149.

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