Unveiling a novel cancer hallmark by evaluation of neural infiltration in cancer

Cancer cells acquire necessary functional capabilities for malignancy through the influence of the nervous system. We evaluate the extent of neural infiltration within the tumor microenvironment (TME) across multiple cancer types, highlighting its role as a cancer hallmark. We identify cancer-related neural genes using 40 bulk RNA-seq datasets across 10 cancer types, developing a predictive score for cancer-related neural infiltration (C-Neural score). Cancer samples with elevated C-Neural scores exhibit perineural invasion, recurrence, metastasis, higher stage or grade, or poor prognosis. Epithelial cells show the highest C-Neural scores among all cell types in 55 single-cell RNA sequencing datasets. The epithelial cells with high C-Neural scores (epi-highCNs) characterized by increased copy number variation, reduced cell differentiation, higher epithelial-mesenchymal transition scores, and elevated metabolic level. Epi-highCNs frequently communicate with Schwann cells by FN1 signaling pathway. The co-culture experiment indicates that Schwann cells may facilitate cancer progression through upregulation of VDAC1. Moreover, C-Neural scores positively correlate with the infiltration of antitumor immune cells, indicating potential response for immunotherapy. Melanoma patients with high C-Neural scores may benefit from trametinib. These analyses illuminate the extent of neural influence within TME, suggesting potential role as a cancer hallmark and offering implications for effective therapeutic strategies against cancer.