Aerobic exercise inhibits lung adenocarcinoma invasion dependent on the superior cervical ganglion

To elucidate possible neural and molecular pathway mechanisms underlying the suppression of aerobic exercise in lung adenocarcinoma (LUAD) invasion. Sympathetic nerve distribution was visualized via immunofluorescent staining in human tissue microarrays (TMAs) and mouse lung specimens. Pseudorabies virus (PRV) retrograde tracing method was employed to identify the brain-lung neural circuit, and superior cervical ganglionectomy was administrated to achieve pulmonary sympathetic denervation. Voluntary wheel running (VWR) worked as an aerobic exercise to intervene the brain-lung neural circuit to suppress mouse LUAD invasion. Norepinephrine (NE) levels and the expression of ADRB2 and MMP2 were assessed using ELISA, Western blot and qRT-PCR methods. RNA sequencing, along with transwell and wound-healing assays, were conducted on lentiviral-mediated ADRB2-overexpressing LUAD cells to evaluate migratory and invasive behaviors. Substantial sympathetic nerve infiltration was detected in both human and mouse LUAD specimens, with a negative correlation observed between intratumoral sympathetic nerve density and tumor volume. Retrograde tracing revealed that pulmonary sympathetic nerves are predominantly innervated by the superior cervical ganglion (SCG). SCG resection abrogated the exercise-induced elevation in intratumoral NE and reversed the anti-invasion benefits of exercise. In vitro, NE treatment downregulated MMP2 expression and impaired the migration and invasion of LUAD cells. Similarly, ADRB2 overexpression suppresses LUAD invasion by inhibiting MMP2 expression. The SCG acts as a relay hub connecting higher brain centers to intratumoral sympathetic activity, and VWR engages this SCG-mediated pathway to exert an anti-invasive effect on LUAD invasion. VWR stimulates NE release from intratumoral sympathetic nerves in LUAD. NE inhibits LUAD invasion via the ADRB2-MMP2 signaling pathway. SCG-dependent sympathetic pathway regulates LUAD invasion In lung metastasis model, the SCG served as a critical relay node connecting intratumoral sympathetic nerves with upstream brain regions. VWR promotes the release of NE from intratumoral sympathetic nerve terminals, which act on β2-adrenoceptors on tumor cells, downregulates MMP2 expression, inhibits extracellular matrix degradation, and thereby inhibits tumor invasion. Surgical removal of the SCG reverses the anti-invasive effect of VWR, indicating that exercise-induced suppression of tumor invasion relies on an intact brain–SCG–sympathetic nerve pathway.