Neuronal substance P drives metastasis through an extracellular RNA-TLR7 axis

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Item Type:	Article
Title:	Neuronal substance P drives metastasis through an extracellular RNA-TLR7 axis
Creators Name:	Padmanaban, V., Keller, I., Seltzer, E.S., Ostendorf, B.N., Kerner, Z. and Tavazoie, S.F.
Abstract:	Tumour innervation is associated with worse patient outcomes in multiple cancers, which suggests that it may regulate metastasis. Here we observed that highly metastatic mouse mammary tumours acquired more innervation than did less-metastatic tumours. This enhanced innervation was driven by expression of the axon-guidance molecule SLIT2 in tumour vasculature. Breast cancer cells induced spontaneous calcium activity in sensory neurons and elicited release of the neuropeptide substance P (SP). Using three-dimensional co-cultures and in vivo models, we found that neuronal SP promoted breast tumour growth, invasion and metastasis. Moreover, patient tumours with elevated SP exhibited enhanced lymph node metastatic spread. SP acted on tumoral tachykinin receptors (TACR1) to drive death of a small population of TACR1 cancer cells. Single-stranded RNAs (ssRNAs) released from dying cells acted on neighbouring tumoural Toll-like receptor 7 (TLR7) to non-canonically activate a prometastatic gene expression program. This SP- and ssRNA-induced Tlr7 gene expression signature was associated with reduced breast cancer survival outcomes. Therapeutic targeting of this neuro-cancer axis with the TACR1 antagonist aprepitant, an approved anti-nausea drug, suppressed breast cancer growth and metastasis in multiple models. Our findings reveal that tumour-induced hyperactivation of sensory neurons regulates multiple aspects of metastatic progression in breast cancer through a therapeutically targetable neuropeptide/extracellular ssRNA sensing axis.
Keywords:	Breast Neoplasms, Cell Death, Membrane Glycoproteins, Neoplasm Invasiveness, Neoplasm Metastasis, Neoplastic Gene Expression Regulation, RNA, Sensory Receptor Cells, Substance P, Tachykinin Receptors, Toll-Like Receptor 7, Tumor Cell Line, Animals, Mice
Source:	Nature
ISSN:	0028-0836
Publisher:	Nature Publishing Group
Volume:	633
Number:	8028
Page Range:	207-215
Date:	5 September 2024
Official Publication:	https://doi.org/10.1038/s41586-024-07767-5
PubMed:	View item in PubMed

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