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

in Cancer cell by 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 Park, Myung Jin Park, Do-Hyun Nam, Jeongwu Lee

TLDR

  • The study found that a protein called F3 is important for the growth and spread of a type of brain tumor called glioblastoma. The study found that F3 is produced in cells that become senescent (slow-growing) after radiation therapy. F3 helps these cells grow and spread by changing the way the cells work and by making the environment around the cells more favorable for the cells to grow. The study also found that F3 can help the cells become more like a different type of cell called a mesenchymal cell, which can help the tumor spread. The study found that a new drug that targets F3 can stop these changes and prevent the tumor from spreading. The study suggests that this drug could be used to treat glioblastoma in the future.

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-βGalGBM 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.

Overview

  • The study investigates the impact of radiation therapy (RT) on glioblastoma (GBM) and its microenvironment (TME).
  • The study identifies CD142 (tissue factor or F3) as a robustly induced cell surface marker in senescence-associated β-galactosidase (SA-βGal)-positive GBM cells after irradiation. F3 promotes clonal expansion and orchestrates oncogenic TME remodeling. 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 these oncogenic events and impedes tumor relapse in vivo. The study aims to identify F3 as a critical regulator for therapeutic resistance and oncogenic senescence in GBM, opening potential therapeutic avenues.

Comparative Analysis & Findings

  • The study compares the outcomes observed under different experimental conditions or interventions, specifically the impact of radiation therapy on GBM and its microenvironment. The study identifies CD142 (tissue factor or F3) as a robustly induced cell surface marker in senescence-associated β-galactosidase (SA-βGal)-positive GBM cells after irradiation. F3 promotes clonal expansion and orchestrates oncogenic TME remodeling. F3-mediated focal hypercoagulation states lead to activation of tumor-associated macrophages (TAMs) and extracellular matrix (ECM) remodeling. The study finds that F3 is a critical regulator for therapeutic resistance and oncogenic senescence in GBM, opening potential therapeutic avenues.

Implications and Future Directions

  • The study's findings have significant implications for the field of research and clinical practice. The study identifies F3 as a critical regulator for therapeutic resistance and oncogenic senescence in GBM, opening potential therapeutic avenues. The study suggests that F3-targeting agents could be used to inhibit oncogenic events and impede tumor relapse in vivo. The study identifies several limitations, including the need for further research to validate the findings in larger patient populations and to explore the potential of F3-targeting agents in combination with other therapies. The study suggests several future research directions, including the development of more specific F3-targeting agents and the exploration of the role of F3 in other types of cancer.
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