Related Experiment Video
Updated: Mar 20, 2026
Author Spotlight: Innovative Cancer Therapies with Iron Oxide Nanoparticles for Glioblastoma Treatment
Published on: September 27, 2024
NANP targeting radiosensitizes glioblastoma through TNFR1 sialylation-driven mesenchymal shift
Yingwen Ding1,2,3, Ze-Yan Zhang1,2,3, Ravesanker Ezhilarasan2,3
1School of Basic Medical Sciences, Institute of Biomedical Innovation, The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, Provincial Key Laboratory of Tumor Biology, Jiangxi Medical College, Nanchang University, Nanchang, China.
Abstract:
Glioblastoma (GBM) patients have dismal survival due to resistance to initial ionizing radiation therapy (RT). Clonal evolution analysis reveals no dominant RT-resistant clones, prompting a genome-wide CRISPR screen to identify radiosensitizing targets. The screening highlights DNA damage response genes, validating the effectiveness of our approach. N-acylneuraminate-9-phosphatase (NANP), a critical enzyme in the sialic acid synthetic pathway, is top-ranked in the screening and associated with patient outcomes. After radiation, NANP-deficient cells exhibit more DNA damage, G2/M arrest and apoptosis, and impaired DNA repair by favoring non-homologous end-joining over homologous recombination. Mechanistically, NANP influences NF-κB signaling and the mesenchymal state by modulating sialylation and internalization of tumor necrosis factor receptor 1 (TNFR1), thereby affecting RT sensitivity. Intracranial orthotopic xenograft experiments validate the function of NANP in vivo. Here, we identify NANP as a radiosensitizing target dependent on TNFR1 sialylation and mesenchymal shift, providing a basis for developing RT sensitizers for GBM.
Insights
Glioblastoma (GBM) patients often resist radiation therapy (RT). Researchers found N-acylneuraminate-9-phosphatase (NANP) deficiency increases DNA damage and RT sensitivity, identifying NANP as a potential radiosensitizing target for GBM treatment.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Glioblastoma (GBM) exhibits poor survival rates due to resistance to ionizing radiation therapy (RT).
- Identifying novel targets to overcome RT resistance is crucial for improving GBM patient outcomes.
Purpose of the Study:
- To identify novel radiosensitizing targets in Glioblastoma using a genome-wide CRISPR screen.
- To elucidate the mechanism by which N-acylneuraminate-9-phosphatase (NANP) affects radiation sensitivity in GBM.
Main Methods:
- Genome-wide CRISPR screening to identify radiosensitizing targets.
- Analysis of DNA damage response, cell cycle progression, apoptosis, and DNA repair pathways in NANP-deficient cells.
- Investigation of NANP's role in NF-κB signaling, TNFR1 sialylation, and mesenchymal transition.
- In vivo validation using intracranial orthotopic xenograft models.
Main Results:
- CRISPR screening identified DNA damage response genes as key radiosensitizing targets.
- N-acylneuraminate-9-phosphatase (NANP) was top-ranked and associated with patient outcomes.
- NANP deficiency led to increased DNA damage, G2/M arrest, apoptosis, and impaired homologous recombination repair after radiation.
- NANP modulates RT sensitivity via TNFR1 sialylation and NF-κB signaling, promoting a mesenchymal state.
Conclusions:
- NANP is a critical radiosensitizing target in Glioblastoma.
- NANP's function in radiosensitization is linked to TNFR1 sialylation and mesenchymal transition.
- Targeting NANP offers a potential strategy for developing novel radiation sensitizers for GBM treatment.
More Related Videos
08:57Author Spotlight: Genetically Engineered Mouse Models and Pathological Characterization of Neurofibromatosis Type 1 Associated Tumors
Published on: May 17, 2024
09:33Author Spotlight: Finding New Therapeutic Targets for Malignant Peripheral Nerve Sheath Tumor Through Genome-Scale shRNA Screens
Published on: August 25, 2023