Fig. 6: Impact of the circadian clock on cell motility in GBM.

Migration, invasion, chemotaxis, and EMT are affected by the molecular clock. Migration and invasion enable cancer cells to form local or distant metastasis. Especially invasion allows them to cross through the extracellular matrix, which is a crucial step for metastasis. Chemotaxis is referred to as the sensing of certain signals, so-called chemo-attractants, which enable directed migration and invasion. EMT is a transcriptional program regulated by a set of master transcription factors. It enables cancer cells to acquire a mesenchymal and an infiltrative phenotype. REV-ERBβ positively affects cell motility by increasing the expression and membrane localization of the receptor tyrosine kinase AXL. AXL induces the EMT master transcription factor SLUG (Neural crest transcription factor Slug Protein snail (D. melanogaster Snail zinc-finger transcriptional repressor) homolog 2), as well as AKT, CDC42 (Cell Division Cycle 42) and RAC to promote migration, invasion and chemotaxis. REV-ERBβ can also induce CDC42 and RAC independent on AXL. Further, it has a positive impact on FAK (Focal Adhesion Kinase) and positively influences the actin network, but it has a negative impact on FABP7-dependent migration. Focal adhesion as induced by FAK enables cells to tightly anchor themselves to the extracellular matrix, which induces several downstream signalling pathways linked to tumorigenesis. VASP is implicated in the elongation of actin filaments and P-Cofilin in the severing of F-actin filaments. Hence, both proteins are important regulators of the actin network dynamic. This dynamic is important for cell motility. PER2 inhibits AKT-dependent migration and invasion via activation of PTEN. CLOCK/BMAL1 are positive regulators of the actin network. They induce the expression of VASP (Vasodilator-stimulated phosphoprotein) and P-Cofilin. BMAL1 is a negative regulator of AKT-dependent migration and invasion. CLOCK positively influences NF-κB-dependent EMT. Other clock proteins are also implicated in the regulation of EMT, but the mechanism is unclear. The clock network as a whole has a positive influence on EMT. The clock network also controls the rhythmicity of the RAC-GEF TIAM1 and therefore of the migration capacity of the tumour cell. GEFs (Guanine Exchange Factors) are activators of small GTPases such as RAC. The figure was created with BioRender.com.