The paracrine TAC1-TACR1 signaling promotes endothelial senescence and metastatic progression in neuroblastoma

Distal metastasis remains a major clinical challenge in neuroblastoma (NB), the most common extracranial solid tumor in children. However, the molecular mechanisms mediating tumor-endothelial crosstalk and NB metastasis remain incompletely understood. By integrating single-cell omics analyses of clinical NB samples with experimental validations, we established the molecular subtypes of NB and identified a C2 subtype marked by MYCN amplification and dual positivity for TWIST1 and TAC1 expressions. This aggressive tumor subpopulation exhibited enhanced secretion of the neuropeptide substance P (encoded by TAC1), which was regulated by the transcription factor TWIST1. TAC1 signaled to tumor-associated endothelial cells with elevated TACR1 expression, consequently leading to endothelial senescence and disrupted vascular integrity. Remarkably, TAC1 overexpression was sufficient to accelerate NB tumorigenesis, circulating tumor cell (CTC) generation and metastatic progression in vivo. Clinically, TWIST1⁺TAC⁺ CTCs were significantly enriched in the blood samples of metastatic NB patients compared to the non-metastatic group. As a proof-of-principle study, we further demonstrated that the TACR1 antagonist aprepitant could effectively suppress endothelial senescence, tumorigenesis, and CTC-mediated metastatic progression in vivo, presenting a potential therapeutic strategy for NB patients with TAC1-TACR1 activation.