Integration analysis of single-cell transcriptome reveals specific monocyte subsets associated with melanoma brain and leptomeningeal metastasis.

Abstract

Melanoma central nervous system (CNS) metastasis remains a leading cause of patient mortality, and the underlying pathological mechanism has not been fully elucidated, leading to a lack of effective therapeutic strategies. In this study, we conducted an integrated analysis of single-cell transcriptomic data related to melanoma brain metastasis (MBM) and leptomeningeal metastasis (LMM). We focused on differences of subset composition and molecular expression of monocytes in blood, primary tumor, brain metastases, and leptomeningeal metastases. Significant differences were observed among monocytes in blood, primary tumor, and different CNS metastatic tissues, particularly in terms of subset differentiation and gene expression patterns. Subsequent analysis revealed the upregulation of cell proportions of six monocyte subsets in brain metastasis and leptomeningeal metastasis. Based on differential gene analysis, four of these subsets exhibited increased expression of factors promoting tumor migration and survival, including AREG+ monocytes (AREG, EREG, THBS1), FABP5+ monocytes (SPP1, CCL2, CTSL), and CXCL3+ monocytes (CXCL3, IL8, IL1B). The proportions of TPSB2+ monocytes (IL32, CCL5) were notably elevated in melanoma leptomeningeal metastasis tissues. Pathway analysis indicated the activation of signaling pathways such as NOD-like receptors, NFκB, and Toll-like receptors in these metastasis-related subsets. Our findings elucidate that AREG+, FABP5+ and CXCL3+ monocytes are associated with brain metastasis and TPSB2+ monocytes are associated with leptomeningeal metastasis in melanoma, which may be contribute to the development of therapeutic strategies focusing on monocytes or cytokines for melanoma CNS metastasis.