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

Hye Min Jeon, Jeong Yub Kim, Hee Jin Cho, Won Jun Lee, Dayna Nguyen, Sung Soo Kim, Young Taek Oh, Hee Jin Kim, Chan Woong Jung, Gonzalo Pinero, Tanvi Joshi, Dolores Hambardzumyan, Takuya Sakaguchi, Christopher G. Hubert, Thomas M. McIntyre, Howard A. Fine, Candece L. Gladson, Bingcheng Wang, Benjamin W. Purow, Jong Bae ParkMyung Jin Park, Do Hyun Nam, Jeongwu Lee

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

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.

Original languageEnglish
Pages (from-to)1480-1497.e9
JournalCancer Cell
Volume41
Issue number8
DOIs
StatePublished - 14 Aug 2023

Keywords

  • glioblastoma
  • senescence
  • therapeutic resistance
  • tissue factor
  • tumor microenvironment

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