Systematic characterization of neurotransmitter receptor dysregulation identifies a neural-related prognostic signature associated with biochemical recurrence in prostate cancer.

Abstract

BACKGROUND: The nervous system is increasingly recognized to play a critical role in tumor initiation and progression. Central to this complex relationship are the interactions between neurotransmitters secreted by neurons and their receptors (neurotransmitter receptors, NTRs) expressed on cancer cells, which activate multiple intracellular signaling pathways. However, the spectrum of NTR dysregulation and its association with biochemical recurrence (BCR) in prostate cancer (PCa) has not been explored. Therefore, the aim of this study was to fill this gap. METHODS: We systematically characterized the expression profiles of 130 NTR genes by integrating bulk and single-cell transcriptomic data. Consistently dysregulated NTR (cdNTR) genes were identified and used to construct a PCa signature (PCaSig) using elastic-net regression. The robustness of PCaSig was evaluated across three independent cohorts. In addition, the associations of PCaSig with clinicopathological characteristics, genomic alterations, tumor immune-related characteristics, and biological pathways were comprehensively investigated. RESULTS: Thirteen cdNTR genes with strong cell-type specificity, particularly in luminal epithelial cells, were identified. PCaSig robustly stratified patients into distinct BCR risk groups across multiple independent cohorts and remained an independent predictor after adjustment for clinicopathological factors. High PCaSig scores were associated with aggressive clinicopathological features, elevated tumor mutation burden (TMB), suppression of neurotransmitter-related signaling, and activation of cell-cycle and immune-related pathways. Notably, PCaSig refined prognostic stratification regardless of TMB status and was associated with distinct immune-related characteristics, including immune checkpoint expression and immune cell infiltration. Incorporation of PCaSig into a clinical nomogram significantly improved prognostic accuracy and clinical net benefit. CONCLUSIONS: These findings establish NTR dysregulation as a previously underappreciated dimension of PCa and support PCaSig as a clinically relevant tool for personalized management.