A proteasome-resistant fragment of NIK mediates oncogenic NF-κB signaling in schwannomas

Schwannomas are common, highly morbid and medically untreatable tumors that can arise in patients with germ line as well as somatic mutations in neurofibromatosis type 2 (NF2). These mutations most commonly result in the loss of function of the NF2-encoded protein, Merlin. Little is known about how Merlin functions endogenously as a tumor suppressor and how its loss leads to oncogenic transformation in Schwann cells (SCs). Here, we identify nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-inducing kinase (NIK) as a potential drug target driving NF-κB signaling and Merlin-deficient schwannoma genesis. Using a genomic approach to profile aberrant tumor signaling pathways, we describe multiple upregulated NF-κB signaling elements in human and murine schwannomas, leading us to identify a caspase-cleaved, proteasome-resistant NIK kinase domain fragment that amplifies pathogenic NF-κB signaling. Lentiviral-mediated transduction of this NIK fragment into normal SCs promotes proliferation, survival, and adhesion while inducing schwannoma formation in a novel in vivo orthotopic transplant model. Furthermore, we describe an NF-κB-potentiated hepatocyte growth factor (HGF) to MET proto-oncogene receptor tyrosine kinase (c-Met) autocrine feed-forward loop promoting SC proliferation. These innovative studies identify a novel signaling axis underlying schwannoma formation, revealing new and potentially druggable schwannoma vulnerabilities with future therapeutic potential.

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PMC
Published
2025-10-10
DOI
https://doi.org/10.17615/5jjq-6f18
Primary Topic
Neurofibromatosis and Schwannoma Cases
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article
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article

A proteasome-resistant fragment of NIK mediates oncogenic NF-κB signaling in schwannomas

Karl Staser, Waylan Bessler, Jacquelyn D. Lajiness, Eric Hawley et al.
PMC
Neurofibromatosis and Schwannoma Cases
article

A proteasome-resistant fragment of NIK mediates oncogenic NF-κB signaling in schwannomas

Karl Staser, Waylan Bessler, Jacquelyn D. Lajiness, Eric Hawley, SuJung Park, Timothy Joseph Stuhlmiller, Gary L. Johnson, Donna M. Edwards, D. Wade Clapp, George E. Sandusky, Steven D. Rhodes, Steven P. Angus, Charles W. Yates, Benjamin M. Wahle, Yongzheng He, Grzegorz Nalepa, Abbi E. Smith, Anat Stemmer‐Rachamimov, Shi Chen, Xiaohong Li, Jin Yuan, Jeffrey R. Gehlhausen, Li Jiang, Xianlin Yang
article en

Abstract

Schwannomas are common, highly morbid and medically untreatable tumors that can arise in patients with germ line as well as somatic mutations in neurofibromatosis type 2 (NF2). These mutations most commonly result in the loss of function of the NF2-encoded protein, Merlin. Little is known about how Merlin functions endogenously as a tumor suppressor and how its loss leads to oncogenic transformation in Schwann cells (SCs). Here, we identify nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-inducing kinase (NIK) as a potential drug target driving NF-κB signaling and Merlin-deficient schwannoma genesis. Using a genomic approach to profile aberrant tumor signaling pathways, we describe multiple upregulated NF-κB signaling elements in human and murine schwannomas, leading us to identify a caspase-cleaved, proteasome-resistant NIK kinase domain fragment that amplifies pathogenic NF-κB signaling. Lentiviral-mediated transduction of this NIK fragment into normal SCs promotes proliferation, survival, and adhesion while inducing schwannoma formation in a novel in vivo orthotopic transplant model. Furthermore, we describe an NF-κB-potentiated hepatocyte growth factor (HGF) to MET proto-oncogene receptor tyrosine kinase (c-Met) autocrine feed-forward loop promoting SC proliferation. These innovative studies identify a novel signaling axis underlying schwannoma formation, revealing new and potentially druggable schwannoma vulnerabilities with future therapeutic potential.

PMC
University of North Carolina at Chapel Hill (US), Washington University in St. Louis (US), Massachusetts General Hospital (US), Indiana University School of Medicine, Indiana University – Purdue University Indianapolis (US)
Good health and well-being
Openalex Percentile: Top 100%
Neurofibromatosis and Schwannoma Cases
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