Circadian regulator CLOCK promotes tumor angiogenesis in glioblastoma
Lizhi Pang,
Madeline Dunterman,
Wenjing Xuan,
Annette Gonzalez,
Yiyun Lin,
Wen-Hao Hsu,
Fatima Khan,
Robert S. Hagan,
William A. Muller,
Amy B. Heimberger,
Peiwen Chen
Affiliations
Lizhi Pang
Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
Madeline Dunterman
Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
Wenjing Xuan
Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
Annette Gonzalez
Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
Yiyun Lin
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
Wen-Hao Hsu
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
Fatima Khan
Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
Robert S. Hagan
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
William A. Muller
Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
Amy B. Heimberger
Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
Peiwen Chen
Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Corresponding author
Summary: 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.
