Glioma-derived ULBP2 triggers microglial extracellular traps formation via PAD4 lactylation to drive autophagy-dependent malignant growth

Abstract

The microglial extracellular traps(MiETs) were appeared in glioblastoma multiforme (GBM), but the underlying molecular mechanisms and functions were unknown. In this study, we aimed to explore the ability of GBM-derived UL16-binding protein 2 (ULBP2) on activating MiETs and manipulating microglia to support GBM development. Herein, ULBP2 was identified as a key upregulated protein in GBM and triggered MiETs formation. In turn, MiETs accelerated GBM malignant growth. Mechanistically, GBM released ULBP2 to connect with syndecan-1(SDC1) on microglia, the ULBP2/SDC1 complex induced lactylation of peptidylarginine deiminase 4 (PAD4) and following MiETs formation. Furthermore, MiETs stimulated GBM autophagy to promote proliferation and invasion. Our results demonstrated that GBM exerted a crucial role in MiETs formation through the ULBP2/SDC1/PAD4-Kla axis, and the interaction between GBM and microglia created a feed-forward mechanism for tumor progression. Thus, these data provided novel insights into a potential therapeutic target toward MiETs for preventing and suppressing GBM. Glioblastoma(GBM) regulates non-tumor cells in tumor microenvironment to manipulate malignant growth of tumor. In this study, interaction mechanisms between GBM and microglia were investigated. The clinical samples analysis, cellular research and animal experiment were performed. Many biomedical technologies were applied, such as immunohistochemistry, immunofluorescence, co-immunoprecipitation, western blot, lentiviral transfection, CCK8, transwell chamber and so on. We found that GBM generated ULBP2 to trigger PAD4-Kla in microglia and following microglial extracellular traps(MiETs). Next, the MiETs contributed to accelerating GBM proliferation and invasion. Our identification supported that GBM-derived ULBP2 participated in crosstalk between GBM and microglia. Furthermore, targeting ULBP2-originated positive feedback pathway between GBM and microglia will be a prominent achievement for GBM treatment.

The authors' abstract, as published at the source. Oncogene, 2026 · DOI ↗