scRNA-seq and spatial transcriptomics reveal neuroendocrine-like cancer cells promote angiogenesis and EMT through neural signaling pathways in male breast cancer

Abstract Male breast cancer (MBC) is a relatively rare and inadequately researched disease, and its cellular and molecular traits remain obscure. In this study, we conducted single-cell sequencing (N=20) and spatial transcriptomics (N=14) on 34 fresh tissue samples from 27 MBC patients. We identified six major cancer cell subtypes that are associated with the development and progression of MBC. Specifically, cancer cells exhibiting neuroendocrine-like properties facilitate immune evasion, tumor angiogenesis, epithelial-to-mesenchymal transition, cell proliferation, tumor invasion, and metastasis. They do so by secreting neuro-related factors and engaging in regulating neuro-related signaling pathways, synergistically interacting with T cells, macrophages, and fibroblasts within the tumor microenvironment. Additionally, we found that mutations or copy number variations amplifications of the UTY gene on the Y chromosome and/or its high transcript expression are closely associated with adverse clinical outcomes in male cancer patients, including MBC patients. In conclusion, our study provides important data support for a deeper understanding of the molecular characteristics and tumor microenvironment of MBC, and offers important clues for developing improved therapeutic strategies to improve the prognosis of MBC patients.