Padmanaban, V.; Keller, I.; Seltzer, E. S.; Ostendorf, B. N.; Kerner, Z.; Tavazoie, S. F.

Increased tumour innervation is associated with adverse survival outcomes in multiple cancers (1-4). To better understand the mechanisms underlying this, we studied the impact of innervation on breast cancer metastatic progression. Metastatic mammary tumours of mice were substantially more innervated than non-metastatic isogenic tumours. Three dimensional co-cultures and in vivo models revealed that sensory dorsal root ganglion (DRG) neurons enhanced the growth, invasion, and systemic dissemination of cancer cells - thereby driving breast cancer metastasis. By in vitro screening of neuropeptides known to be secreted by DRG neurons, we identified substance-P (SP) as a mediator of these pro-metastatic functions. Neuronal SP signaled through tumoural tachykinin receptors (TACR1) to drive single-stranded RNA (ssRNA) secretion from cancer cells. Extracellular RNA acted on tumoural TLR7 receptors to activate an autocrine pro-metastatic gene expression program. In support of these findings, patient tumours with increased SP expression exhibited higher rates of lymph node metastasis. Additionally, this SP/ssRNA induced Tlr7 gene expression signature associated with reduced breast cancer survival outcomes in two independent patient cohorts. Finally, therapeutic targeting of this neuro-cancer axis with the TACR1 antagonist aprepitant, an approved anti-nausea drug, suppressed breast cancer metastasis in multiple mouse models. Our findings reveal multiple aspects of metastatic progression to be regulated by neurons via a therapeutically targetable neuropeptide/extracellular RNA sensing axis.