美国洛克菲勒大学Sohail F. Tavazoie团队发现，神经肽P通过细胞外RNA-TLR7轴驱动转移。这一研究成果于2024年8月7日在线发表在国际学术期刊《自然》上。

研究人员观察到，高转移性的小鼠乳腺肿瘤比低转移性肿瘤获得了更多的神经支配。这种增强的神经支配是由肿瘤血管中轴突引导分子SLIT2的表达驱动的。乳腺癌细胞引发感觉神经元的自发钙活动，并促使神经肽P（SP）的释放。

通过三维共培养和体内模型，研究人员发现神经元SP促进了乳腺肿瘤的生长、侵袭和转移。此外，SP水平升高的患者肿瘤表现出增强的淋巴结转移扩散。SP通过作用于肿瘤性速激肽受体（TACR1）导致少量TACR1高表达癌细胞的死亡。来自死亡细胞的单链RNA（ssRNA）作用于邻近的肿瘤性Toll样受体7（TLR7），以非经典方式激活促转移基因表达程序。这个SP和ssRNA诱导的Tlr7基因表达特征与乳腺癌生存结果降低相关。

使用TACR1拮抗剂阿瑞匹坦（一种批准的抗恶心药物）治疗，可以在多个模型中抑制乳腺癌的生长和转移。该研究揭示了肿瘤诱导的感觉神经元过度激活通过可治疗的神经肽/细胞外ssRNA感应轴调节乳腺癌的多个转移进程。

据介绍，肿瘤神经化与多种癌症中的较差患者预后相关，这表明它可能调节转移。

附：英文原文

Title: Neuronal substance P drives metastasis through an extracellular RNA–TLR7 axis

Author: Padmanaban, Veena, Keller, Isabel, Seltzer, Ethan S., Ostendorf, Benjamin N., Kerner, Zachary, Tavazoie, Sohail F.

Issue&Volume: 2024-08-07

Abstract: Tumour innervation is associated with worse patient outcomes in multiple cancers1,2, 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 TACR1high 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.

DOI: 10.1038/s41586-024-07767-5

Source: https://www.nature.com/articles/s41586-024-07767-5