Metastatic Cancers Exploit Vagal Sensory Neurons and Neural Repair Programs to Colonize New Tissues

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.