Journal Article

DZNE-2020-01102

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png KLF4K409Q–mutated meningiomas show enhanced hypoxia signaling and respond to mTORC1 inhibitor treatment

von Spreckelsen, N. ; Waldt, N. ; Poetschke, R. ; Kesseler, C. ; Dohmen, H. ; Jiao, H.-K. ; Nemeth, A. ; Schob, S. ; Scherlach, C. ; Sandalcioglu, I. E. ; Deckert, M. ; Angenstein, F.DZNE* ; Krischek, B. ; Stavrinou, P. ; Timmer, M. ; Remke, M. ; Kirches, E. ; Goldbrunner, R. ; Chiocca, E. A. ; Huettelmaier, S. ; Acker, T. ; Mawrin, C. (Corresponding author)

2020
Biomed Central London

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Please use a persistent id in citations: doi:10.1186/s40478-020-00912-x

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 KLF4K409Q mutated tumors harbor an upregulation of hypoxia dependent pathways. Detailed in vitro investigation further showed that the KLF4K409Q mutation induces HIF-1α through the reduction of prolyl hydroxylase activity and causes an upregulation of downstream HIF-1α targets. Finally, we demonstrate that KLF4K409Q mutated tumors are susceptible to mTOR inhibition by Temsirolimus. Taken together, our data link the KLF4K409Q 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.

Keyword(s): Animals (MeSH) ; Cell Line, Tumor (MeSH) ; Cell Proliferation (MeSH) ; Gene Expression Regulation, Neoplastic: drug effects (MeSH) ; Gene Expression Regulation, Neoplastic: genetics (MeSH) ; Humans (MeSH) ; Hypoxia: genetics (MeSH) ; Hypoxia: metabolism (MeSH) ; Hypoxia-Inducible Factor 1, alpha Subunit: drug effects (MeSH) ; Hypoxia-Inducible Factor 1, alpha Subunit: genetics (MeSH) ; Hypoxia-Inducible Factor 1, alpha Subunit: metabolism (MeSH) ; Kruppel-Like Factor 4 (MeSH) ; Kruppel-Like Transcription Factors: drug effects (MeSH) ; Kruppel-Like Transcription Factors: genetics (MeSH) ; Mechanistic Target of Rapamycin Complex 1: antagonists & inhibitors (MeSH) ; Meningeal Neoplasms: genetics (MeSH) ; Meningeal Neoplasms: metabolism (MeSH) ; Meningioma: genetics (MeSH) ; Meningioma: metabolism (MeSH) ; Mice (MeSH) ; Mice, Nude (MeSH) ; Mutation (MeSH) ; Neoplasm Transplantation (MeSH) ; Prolyl Hydroxylases (MeSH) ; Protein Kinase Inhibitors: pharmacology (MeSH) ; RNA-Seq (MeSH) ; Reverse Transcriptase Polymerase Chain Reaction (MeSH) ; Signal Transduction (MeSH) ; Sirolimus: analogs & derivatives (MeSH) ; Sirolimus: pharmacology (MeSH) ; Skull Base Neoplasms (MeSH) ; Tumor Hypoxia: genetics (MeSH) ; Up-Regulation (MeSH)

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Contributing Institute(s):

1. Functional Neuroimaging (AG Angenstein)

Research Program(s):

1. 344 - Clinical and Health Care Research (POF3-344) (POF3-344)

Appears in the scientific report 2020

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