Circadian regulator CLOCK promotes tumor angiogenesis in glioblastoma

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-induc-ible factor 1-alpha (HIF1a)-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 endo-thelial 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.

Automated summary

It has been found that the clock gene regulates the activity of glioma stem cells and affects the development of glioblastoma. The clock gene directs the expression of OLFML3, which leads to the upregulation of POSTN through HIF1a and subsequently promotes tumor angiogenesis through activation of the TBK1 signaling pathway. Blocking the CLOCK-directed POSTN-TBK1 axis has been shown to inhibit tumor progression and angiogenesis.