1. IFI35 regulates non-canonical NF-κB signaling to maintain glioblastoma stem cells and recruit tumor-associated macrophages.
- Author
-
Li D, Wang X, Chen K, Shan D, Cui G, Yuan W, Lin Q, Gimple RC, Dixit D, Lu C, Gu D, You H, Gao J, Li Y, Kang T, Yang J, Yu H, Song K, Shi Z, Fan X, Wu Q, Gao W, Zhu Z, Man J, Wang Q, Lin F, Tao W, Mack SC, Chen Y, Zhang J, Li C, Zhang N, You Y, Qian X, Yang K, Rich JN, Zhang Q, and Wang X
- Subjects
- Humans, Animals, Mice, Brain Neoplasms pathology, Brain Neoplasms metabolism, Brain Neoplasms genetics, Cell Line, Tumor, Tumor Microenvironment, Glioblastoma metabolism, Glioblastoma pathology, Glioblastoma genetics, Signal Transduction, Neoplastic Stem Cells metabolism, Neoplastic Stem Cells pathology, Tumor-Associated Macrophages metabolism, Tumor-Associated Macrophages pathology, NF-kappa B metabolism
- Abstract
Glioblastoma (GBM) is the most aggressive malignant primary brain tumor characterized by a highly heterogeneous and immunosuppressive tumor microenvironment (TME). The symbiotic interactions between glioblastoma stem cells (GSCs) and tumor-associated macrophages (TAM) in the TME are critical for tumor progression. Here, we identified that IFI35, a transcriptional regulatory factor, plays both cell-intrinsic and cell-extrinsic roles in maintaining GSCs and the immunosuppressive TME. IFI35 induced non-canonical NF-kB signaling through proteasomal processing of p105 to the DNA-binding transcription factor p50, which heterodimerizes with RELB (RELB/p50), and activated cell chemotaxis in a cell-autonomous manner. Further, IFI35 induced recruitment and maintenance of M2-like TAMs in TME in a paracrine manner. Targeting IFI35 effectively suppressed in vivo tumor growth and prolonged survival of orthotopic xenograft-bearing mice. Collectively, these findings reveal the tumor-promoting functions of IFI35 and suggest that targeting IFI35 or its downstream effectors may provide effective approaches to improve GBM treatment., (© 2024. The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.)
- Published
- 2024
- Full Text
- View/download PDF