Circadian regulator CLOCK promotes tumor angiogenesis in glioblastoma
- Cell Rep. 2023 Feb 28;42(2):112127. doi: 10.1016/j.celrep.2023.112127.
- 1. Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
- 2. Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
- 3. Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; UTHealth Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- 4. UTHealth Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
- 5. Division of Pulmonary Diseases and Critical Care Medicine, Department of Medicine, Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
- 6. Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. Electronic address: [email protected].
Glioblastoma (GBM) is one of the most aggressive tumors in the adult central nervous system. We previously revealed that circadian regulation of glioma stem cells (GSCs) affects GBM hallmarks of immunosuppression and GSC maintenance in a paracrine and autocrine manner. Here, we expand the mechanism involved in angiogenesis, another critical GBM hallmark, as a potential basis underlying CLOCK's pro-tumor effect in GBM. Mechanistically, CLOCK-directed olfactomedin like 3 (OLFML3) expression results in hypoxia-inducible factor 1-alpha (HIF1α)-mediated transcriptional upregulation of periostin (POSTN). As a result, secreted POSTN promotes tumor angiogenesis via activation of the TANK-binding kinase 1 (TBK1) signaling in endothelial cells. In GBM mouse and patient-derived xenograft models, blockade of the CLOCK-directed POSTN-TBK1 axis inhibits tumor progression and angiogenesis. Thus, the CLOCK-POSTN-TBK1 circuit coordinates a key tumor-endothelial cell interaction and represents an actionable therapeutic target for GBM.