IFI35 regulates non-canonical NF-κB signaling to maintain glioblastoma stem cells and recruit tumor-associated macrophages.

in Cell death and differentiation by Daqi Li, Xiefeng Wang, Kexin Chen, Danyang Shan, Gaoyuan Cui, Wei Yuan, Qiankun Lin, Ryan C Gimple, Deobrat Dixit, Chenfei Lu, Danling Gu, Hao You, Jiancheng Gao, Yangqing Li, Tao Kang, Junlei Yang, Hang Yu, Kefan Song, Zhumei Shi, Xiao Fan, Qiulian Wu, Wei Gao, Zhe Zhu, Jianghong Man, Qianghu Wang, Fan Lin, Weiwei Tao, Stephen C Mack, Yun Chen, Junxia Zhang, Chaojun Li, Nu Zhang, Yongping You, Xu Qian, Kailin Yang, Jeremy N Rich, Qian Zhang, Xiuxing Wang

TLDR

  • The study found that a protein called IFI35 helps Glioblastoma (GBM) cells grow and survive by interacting with other cells in the tumor microenvironment (TME). The study also found that targeting IFI35 could potentially help treat GBM. However, the study has limitations and more research is needed to fully understand the role of IFI35 in GBM.

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.

Overview

  • The study focuses on Glioblastoma (GBM), the most aggressive malignant primary brain tumor, and its tumor microenvironment (TME).
  • The hypothesis being tested is that IFI35, a transcriptional regulatory factor, plays a role in maintaining GSCs and the immunosuppressive TME.

Comparative Analysis & Findings

  • The study identified that 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. It also induced recruitment and maintenance of M2-like TAMs in TME in a paracrine manner.

Implications and Future Directions

  • The study's findings suggest that targeting IFI35 or its downstream effectors may provide effective approaches to improve GBM treatment. However, the study has limitations, such as the use of xenograft models, which may not fully capture the complexity of human GBM. Future research should address these limitations and explore the potential of IFI35 as a therapeutic target in human GBM.
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