Tissue factor is a critical regulator of radiation therapy-induced glioblastoma remodeling

Cancer Cell. 2023 Aug 14;41(8):1480-1497.e9. doi: 10.1016/j.ccell.2023.06.007. Epub 2023 Jul 13.

Abstract

Radiation therapy (RT) provides therapeutic benefits for patients with glioblastoma (GBM), but inevitably induces poorly understood global changes in GBM and its microenvironment (TME) that promote radio-resistance and recurrence. Through a cell surface marker screen, we identified that CD142 (tissue factor or F3) is robustly induced in the senescence-associated β-galactosidase (SA-βGal)-positive GBM cells after irradiation. F3 promotes clonal expansion of irradiated SA-βGal+ GBM cells and orchestrates oncogenic TME remodeling by activating both tumor-autonomous signaling and extrinsic coagulation pathways. Intratumoral F3 signaling induces a mesenchymal-like cell state transition and elevated chemokine secretion. Simultaneously, F3-mediated focal hypercoagulation states lead to activation of tumor-associated macrophages (TAMs) and extracellular matrix (ECM) remodeling. A newly developed F3-targeting agent potently inhibits the aforementioned oncogenic events and impedes tumor relapse in vivo. These findings support F3 as a critical regulator for therapeutic resistance and oncogenic senescence in GBM, opening potential therapeutic avenues.

Keywords: glioblastoma; senescence; therapeutic resistance; tissue factor; tumor microenvironment.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Brain Neoplasms* / genetics
  • Brain Neoplasms* / metabolism
  • Brain Neoplasms* / radiotherapy
  • Cell Line, Tumor
  • Glioblastoma* / drug therapy
  • Glioblastoma* / genetics
  • Glioblastoma* / radiotherapy
  • Humans
  • Neoplasm Recurrence, Local
  • Signal Transduction
  • Thromboplastin
  • Tumor Microenvironment

Substances

  • Thromboplastin