Sleep disturbances promote colorectal cancer perineural invasion via GABA-mediated BDNF secretion

Perineural invasion (PNI) is a hallmark of aggressive colorectal cancer (CRC) progression, often leading to poor patient outcomes. Emerging evidence suggests a link between sleep disturbances and cancer progression through neural pathways. In this study, we investigated how sleep disturbances contribute to PNI in CRC via γ-aminobutyric acid (GABA) and brain-derived neurotrophic factor (BDNF). Clinical data revealed that CRC patients with poor sleep quality exhibited higher PNI rates and worse prognoses. Sleep-deprived mice showed increased CNS-derived GABA levels and compromised blood-brain barrier integrity, facilitating peripheral GABA exposure. GABA treatment enhanced CRC cell proliferation, migration, and invasion by upregulating FOS expression, which in turn increased BDNF secretion. Elevated BDNF activated Schwann cells through the TrkB receptor, promoting their proliferation, migration, invasion, and angiogenesis. Knockdown of FOS or inhibition of TrkB mitigated these effects. Additionally, GABA was found to promote FOS transcription via upregulation of EGR1. Our findings unveil a novel mechanism whereby sleep disturbances exacerbate CRC progression through the GABA-EGR1-FOS-BDNF axis, highlighting the importance of sleep quality in CRC management and suggesting potential therapeutic targets to inhibit PNI.