Abstract
<title>Abstract</title> <p>Metastasis remains the leading cause of cancer-related mortality, yet the mechanisms that enable disseminated tumor cells to colonize distant organs remain incompletely understood.1,2 Here, we identify vagal sensory neurons as key facilitators of metastatic outgrowth. Using genetic, pharmacologic, surgical, and tissue-targeted denervation strategies in murine models of metastatic melanoma and breast cancer, we show that depletion of vagal sensory inputs markedly reduces pulmonary colonization. Mechanistically, metastatic cells exploit nerve injury-induced protein 1, NINJ1, to engage vagal afferents and activate a β-catenin-dependent transcriptional program. This interaction increases expression of receptors for growth factors and enables cancer cells to respond to macrophage- and fibroblast-derived trophic signals within the metastatic niche. Unbiased co-immunoprecipitation proteomics revealed that NINJ1 sequesters key components of the β-catenin destruction complex, including DVL1, AXIN1, CK1δ/ε, and CK2. Consequently, the presence of vagal sensory neurons leads to an NINJ1-dependent accumulation of active β-catenin form in cancer cells, while pharmacologic inhibition of β-catenin signaling abolished NINJ1-driven growth factor responsiveness. Together, these findings identify a neuro-metastatic axis in which metastatic cells co-opt a vagal sensory neuron-associated repair program to colonize new tissues. Targeting NINJ1 significantly reduced metastatic outgrowth across multiple cancer models and host backgrounds, indicating a broad therapeutic potential of these findings.</p>