TY - JOUR
T1 - The coding and non-coding transcriptional landscape of subependymal giant cell astrocytomas
AU - Bongaarts, Anika
AU - van Scheppingen, Jackelien
AU - Korotkov, Anatoly
AU - Mijnsbergen, Caroline
AU - Anink, Jasper J.
AU - Jansen, Floor E.
AU - Spliet, Wim G. M.
AU - den Dunnen, Wilfred F. A.
AU - Gruber, Victoria E.
AU - Scholl, Theresa
AU - Samueli, Sharon
AU - Hainfellner, Johannes A.
AU - Feucht, Martha
AU - Kotulska, Katarzyna
AU - Jozwiak, Sergiusz
AU - Grajkowska, Wieslawa
AU - Buccoliero, Anna Maria
AU - Caporalini, Chiara
AU - Giordano, Flavio
AU - Genitori, Lorenzo
AU - Coras, Roland
AU - Blümcke, Ingmar
AU - Krsek, Pavel
AU - Zamecnik, Josef
AU - Meijer, Lisethe
AU - Scicluna, Brendon P.
AU - Schouten-van Meeteren, Antoinette Y. N.
AU - Mühlebner, Angelika
AU - Mills, James D.
AU - Aronica, Eleonora
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85077346139&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/31834371
U2 - https://doi.org/10.1093/brain/awz370
DO - https://doi.org/10.1093/brain/awz370
M3 - Article
C2 - 31834371
SN - 0006-8950
VL - 143
SP - 131
EP - 149
JO - Brain
JF - Brain
IS - 1
ER -