Grant: Project Grant

Perineural invasion (PNI), defined as the spread of cancer cells along nerves, is a major clinical challenge in several malignancies, including skin cancers. PNI complicates disease management and often necessitates aggressive therapeutic interventions, even after surgical resection of the primary tumor and involved nerves. Until recently, however, the consequences of PNI on tumor-associated nerves-particularly those located distant from the primary lesion-and the extent to which these nerves influence tumor progression and resistance to therapy have remained poorly understood. We demonstrated that PNI in melanoma induces profound nerve injury, characterized by axonal degeneration and loss of the protective myelin sheath. This neural damage initiates a transcriptional stress response driven by activating transcription factor 3 (ATF3), which in turn promotes an immunosuppressive tumor microenvironment and reduces responsiveness to cancer therapies. Given the extensive crosstalk at neuro-neoplastic synapses, we hypothesize that malignant melanoma cells actively reprogram both tumor-associated macrophages (TAMs) and tumor-innervating nociceptor neurons to reinforce regulatory, immunosuppressive pathways that favor tumor persistence. To test this hypothesis and establish tumor-innervating neurons as actionable targets to preserve anti-tumor immunity, we aim to: 1. Determine whether the CGRP-RAMP1 signaling axis drives TAM-mediated immunosuppression. 2. Define how nociceptor-TAM crosstalk influences metastatic dissemination. By reframing tumor-associated nerves as active regulators-rather than passive bystanders-of immune suppression and therapeutic resistance, this work seeks to fundamentally advance our understanding of cancer neurobiology. Recognizing aberrant nerve growth and neural remodeling within tumors may prove as transformative for oncology as the discovery of tumor angiogenesis, opening new avenues for cancer treatment and disease management.