1. Comprehensive Breslow thickness (BT)-based analysis to identify biological mechanisms associated with melanoma pathogenesis.
- Author
-
Liu YJ, Liu Q, Li JQ, Ye QW, Yin SY, Liu C, Liu SL, Zou X, and Ji J
- Abstract
Breslow thickness (BT), a parameter measuring the depth of invasion of abnormally proliferating melanocytes, is a key indicator of melanoma severity and prognosis. However, the mechanisms underlying the increase in BT remain elusive. Utilizing data from The Cancer Genome Atlas (TCGA) human skin cutaneous melanoma (SKCM), we identified a set of BT-related molecules and analyzed their expression and genomic heterogeneity across pan-cancerous and normal tissues. Through consensus clustering, we identified two distinct BT phenotypes in melanoma, which exhibited significant differences in clinical, genomic, and immune infiltration characteristics. High BT molecular expression was associated with reduced CD8+ T cell infiltration and poor immunotherapy response, potentially mediated by the Macrophage Migration Inhibitory Factor (MIF) signaling pathway. In vitro experiments confirmed that BT molecules, including TRIM29, SERPINB5, and RAB25, promoted melanoma development through distinct mechanisms. Notably, fibroblast-derived TRIM29 and B-cell-derived RAB25 interacted with SPP1+ monocytes/macrophages via different pathways. Our findings suggest that genomic variations leading to imbalanced expression of BT molecules across cancers contribute to increased BT, which is closely linked to an immunosuppressive microenvironment. The involvement of multiple cell types and complex intercellular interactions underscores the importance of evaluating dynamic cellular crosstalk in the tumor microenvironment to better understand BT increases and develop more effective immunotherapeutic strategies., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The authors declare no conflicts of interest. All authors contributed to data analysis, drafting, or revising of the article; agree on the journal to which the article is being submitted; provided final approval of the version to be published; and agree to be accountable for all aspects of the work. Prior to the commencement of data collection, the first author obtained written consent from all participants concerning participation and subsequent publication of the study results., (Copyright © 2025 Elsevier B.V. All rights reserved.) more...
- Published
- 2025
- Full Text
- View/download PDF