P物质
乳腺癌
转移
癌症研究
癌症
生物
自分泌信号
癌细胞
细胞外
内科学
受体
医学
神经肽
细胞生物学
作者
Veena Padmanaban,Isabel Keller,Ethan S. Seltzer,Benjamin N. Ostendorf,Zachary Kerner,Sohail F. Tavazoie
标识
DOI:10.1101/2024.03.08.584128
摘要
ABSTRACT 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.
科研通智能强力驱动
Strongly Powered by AbleSci AI