1. Tissue factor is a critical regulator of radiation therapy-induced glioblastoma remodeling.
- Author
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Jeon HM, Kim JY, Cho HJ, Lee WJ, Nguyen D, Kim SS, Oh YT, Kim HJ, Jung CW, Pinero G, Joshi T, Hambardzumyan D, Sakaguchi T, Hubert CG, McIntyre TM, Fine HA, Gladson CL, Wang B, Purow BW, Park JB, Park MJ, Nam DH, and Lee J
- Subjects
- Humans, Thromboplastin, Cell Line, Tumor, Neoplasm Recurrence, Local, Signal Transduction, Tumor Microenvironment, Glioblastoma drug therapy, Glioblastoma genetics, Glioblastoma radiotherapy, Brain Neoplasms genetics, Brain Neoplasms radiotherapy, Brain Neoplasms metabolism
- 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., Competing Interests: Declaration of interests H-M.J. and J.L. are co-inventors on a filed patent application for the use of truncated F7 recombinant protein to treat cancer., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2023
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