Twist1 Transferred via Tumor-Derived Extracellular Vehicles to the Brain Induces Depressive-Like Behaviors through Neuronal Morphogenesis

摘要

Objective: Depression is a common comorbidity in cancer patients, but its underlying mechanisms are not fully elucidated. This study investigates whether Twist1, a proto-oncogene enriched in tumor-derived extracellular vesicles(EVs), contributes to cancer-induced depression(CID) by modulating neuronal morphology. Methods: ShTwist1-expressing 4T1 breast cancer cells were established using lentiviral transduction and implanted into mice to generate tumor-bearing models. Depressive-like behaviors were evaluated by behavioral tests. EVs were isolated from tumor-conditioned medium and serum using ultracentrifugation. Twist1 levels in EVs and mPFC were detected by qPCR and western blotting. Functional experiments included intravenous and intranasal EV delivery and lentiviral Twist1 knockdown in the mPFC to determine causality. Results: The present study demonstrated that tumor-derived EVs mediated the inter-organ communication between tumor cells and brain. Pharmacological inhibition of EVs secretion mitigated depressivelike behaviors in tumor-bearing mice. Intravenous or intranasal injection of EVs from tumor cells or serum from tumor-bearing mice into na?ve mice induced a depressive-like phenotype. Further investigation identified tumor-derived EVs Twsit1 as a crucial mediator of cancerinduced dendritic atrophy and depressive-like behaviors in tumor-bearing mice. Knockdown of Twist1 in tumor cells significantly alleviated the detrimental effects of tumor-derived EVs on neuronal morphogenesis and prevented their pro-depressant effects. Conclusion: Tumor-derived EVs containing Twist1 contribute to cancer-induced depression by impairing neuronal morphogenesis, suggesting a potential target for clinical intervention in cancerrelated mood disorders.

关键词

depression / tumor cell / extracellular vehicles(EVs) / Twist1 / neuronal morphogenesis / dendritogenesis / medial prefrontal cortex(mPFC)