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.
Highlights
Meningioma, a tumor arising from arachnoid cap cells, represents the most common primary brain tumor in adults with an incidence of 8.14/100,000 [23]
While the combination of Krueppel like factor 4 (KLF4) and TRAF7 mutations defines the secretory subtype [5] and KLF4K409Q tumors have been shown to be associated with larger peritumoral edema [43], the biological function and molecular mechanisms associated with the KLF4K409Q mutation have not been elucidated
In order to gauge the impact of the KLF4K409Q mutation on cellular pathways, we performed transcriptomic analysis of 7 KLF4K409Q and 10 KLF4wt meningiomas matched by patient sex, age and tumor location
Summary
Meningioma, a tumor arising from arachnoid cap cells, represents the most common primary brain tumor in adults with an incidence of 8.14/100,000 [23]. SMO mutations are associated with the anterior skull base, have been shown to have an Spreckelsen et al Acta Neuropathologica Communications (2020) 8:41 impact on the onset of tumor recurrence [3, 42] and both AKT1E17K and SMO are currently investigated as candidates for targeted therapy (ClinicalTrials.gov: NCT02523014). While the combination of KLF4 and TRAF7 mutations defines the secretory subtype [5] and KLF4K409Q tumors have been shown to be associated with larger peritumoral edema [43], the biological function and molecular mechanisms associated with the KLF4K409Q mutation have not been elucidated
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