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 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.
摘要
在多种癌症中，肿瘤神经支配与患者较差的预后有关，这表明肿瘤神经支配可能调节转移。在这项研究中，我们观察到高转移性小鼠乳腺肿瘤比低转移性肿瘤获得更多的神经支配。这种神经支配的增强是由肿瘤血管中轴突导向分子SLIT2的表达驱动的。乳腺癌细胞诱导感觉神经元的自发钙活动，并引起神经肽P物质（SP）的释放。利用三维共培养和体内模型，我们发现神经元SP促进了乳腺肿瘤的生长、侵袭和转移。此外，SP升高的患者肿瘤表现出更强的淋巴结转移扩散能力。SP作用于肿瘤速激肽受体（TACR1），促使一小部分TACR1高的癌细胞死亡。死亡细胞释放的单链 RNA（ssRNA）作用于邻近的肿瘤Toll样受体7（TLR7），以非典型方式激活了转移基因表达程序。这种由SP和ssRNA诱导的Tlr7基因表达特征与乳腺癌生存率的降低有关。用TACR1拮抗剂阿瑞匹坦（一种已获批准的止吐药物）治疗这一神经-癌症轴，可在多种模型中抑制乳腺癌的生长和转移。我们的研究结果表明，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传感轴调节乳腺癌转移进展的多个方面。
参考文献
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doi: 10.1038/s41586-022-05374-w.
