Uncovering a feedback loop in glioblastoma that reinforces stemness and immunosuppression.

Glioma stem cells (GSCs) are a small subset of self-renewing, plastic, and multipotent neoplastic cells in glioblastoma (GBM) that sit at the apex of a cellular differentiation hierarchy. Elucidating pathways that enhance GSC properties and determine their cell-specific interactions within the immunosuppressive GBM microenvironment are critical for developing effective therapeutic approaches. The CLOCK-BMAL1 complex, which is well known for its activity as a circadian rhythm-regulating transcription factor, plays a critical role in maintaining GSC stemness, and the gene encoding CLOCK was found to be amplified in about 5% of GBM cases. Here, Zhou et al. have uncovered a "symbiotic exclusivity" relationship between CLOCK-BMAL1 and TFPI2, which is also amplified in a small proportion of GBM cases. This relationship forms a HIF-1α/NF-κB P65-mediated positive feedback loop that boosts the proliferative and tumor-enhancing capacities of GSC and immunosuppressive microglia. This self-amplifying regulatory circuit represents an opportunity for intervention to inhibit GBM growth.