von Spreckelsen, Niklas ORCID: 0000-0002-9873-1711, Waldt, Natalie, Poetschke, Rebecca, Kesseler, Christoph, Dohmen, Hildegard, Jiao, Hui-Ke, Nemeth, Attila, Schob, Stefan, Scherlach, Cordula, Sandalcioglu, Ibrahim Erol, Deckert, Martina, Angenstein, Frank, Krischek, Boris, Stavrinou, Pantelis, Timmer, Marco, Remke, Marc, Kirches, Elmar, Goldbrunner, Roland, Chiocca, E. Antonio, Huettelmaier, Stefan, Acker, Till and Mawrin, Christian (2020). KLF4(K409Q)-mutated meningiomas show enhanced hypoxia signaling and respond to mTORC1 inhibitor treatment. Acta Neuropathol. Commun., 8 (1). LONDON: BMC. ISSN 2051-5960

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Abstract

Meningioma represents the most common primary brain tumor in adults. Recently several non-NF2 mutations in meningioma have been identified and correlated with certain pathological subtypes, locations and clinical observations. Alterations of cellular pathways due to these mutations, however, have largely remained elusive. Here we report that the Krueppel like factor 4 (KLF4)-K409Q mutation in skull base meningiomas triggers a distinct tumor phenotype. Transcriptomic analysis of 17 meningioma samples revealed that KLF4(K409Q) mutated tumors harbor an upregulation of hypoxia dependent pathways. Detailed in vitro investigation further showed that the KLF4(K409Q) mutation induces HIF-1 alpha through the reduction of prolyl hydroxylase activity and causes an upregulation of downstream HIF-1 alpha targets. Finally, we demonstrate that KLF4(K409Q) mutated tumors are susceptible to mTOR inhibition by Temsirolimus. Taken together, our data link the KLF4(K409Q) mediated upregulation of HIF pathways to the clinical and biological characteristics of these skull base meningiomas possibly opening new therapeutic avenues for this distinct meningioma subtype.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
von Spreckelsen, NiklasUNSPECIFIEDorcid.org/0000-0002-9873-1711UNSPECIFIED
Waldt, NatalieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Poetschke, RebeccaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kesseler, ChristophUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dohmen, HildegardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jiao, Hui-KeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nemeth, AttilaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schob, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Scherlach, CordulaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sandalcioglu, Ibrahim ErolUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Deckert, MartinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Angenstein, FrankUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krischek, BorisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stavrinou, PantelisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Timmer, MarcoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Remke, MarcUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kirches, ElmarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Goldbrunner, RolandUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chiocca, E. AntonioUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Huettelmaier, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Acker, TillUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mawrin, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-337624
DOI: 10.1186/s40478-020-00912-x
Journal or Publication Title: Acta Neuropathol. Commun.
Volume: 8
Number: 1
Date: 2020
Publisher: BMC
Place of Publication: LONDON
ISSN: 2051-5960
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
ENDOTHELIAL GROWTH-FACTOR; PERITUMORAL BRAIN EDEMA; SKULL BASE MENINGIOMAS; TUMOR-SUPPRESSOR; SECRETORY MENINGIOMAS; STEM-CELLS; KLF4; CANCER; EXPRESSION; MUTATIONSMultiple languages
NeurosciencesMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/33762

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