Tissue factor is a critical regulator of radiation therapy-induced glioblastoma remodeling
Menée in vitro et à l'aide de modèles murins de glioblastome, cette étude met en évidence le rôle du facteur tissulaire (CD142) dans le remodelage du microenvironnement tumoral induit par la radiothérapie
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 ?-galactosidase (SA-?Gal)-positive GBM cells after irradiation. F3 promotes clonal expansion of irradiated SA-?Gal+ 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.
Cancer Cell , article en libre accès, 2022