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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.

Affiliations

Hye-Min Jeon 1, Jeong-Yub Kim 2, Hee Jin Cho 3, Won Jun Lee 1, Dayna Nguyen 1, Sung Soo Kim 4, Young Taek Oh 4, Hee-Jin Kim 2, Chan-Woong Jung 2, Gonzalo Pinero 5, Tanvi Joshi 5, Dolores Hambardzumyan 5, Takuya Sakaguchi 6, Christopher G Hubert 7, Thomas M McIntyre 8, Howard A Fine 9, Candece L Gladson 1, Bingcheng Wang 10, Benjamin W Purow 11, Jong Bae Park 4, Myung Jin Park 2, Do-Hyun Nam 12, Jeongwu Lee 13
1Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
2Divisions of Radiation Cancer Research, Research Center for Radio-Senescence, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
3Department of Biomedical Convergence Science and Technology, Kyungpook National University, Daegu, Korea.
4Department of System Cancer Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Korea.
5Icahn School of Medicine at Mount Sinai, New York, NY, USA.
6Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
7Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
8Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
9Department of Neurology, Weill Cornell Medicine, New York, NY, USA.
10Department of Medicine, MetroHealth Campus, School of Medicine, Case Western Reserve University, Cleveland, OH, USA.
11Department of Neurology, UVA Cancer Center, University of Virginia Health System, Charlottesville, VA, USA.
12Institute for Refractory Cancer Research, Samsung Medical Center, Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Department of Neurosurgery Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
13Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA. Electronic address: leej7@ccf.org.