Integrated single-cell and spatial transcriptomic analyses reveal an aging-associated fibroblast subtype linked to tumor progression in human skin

Abstract

Aging is a major risk factor for the development of many cancers, yet the tissue-level mechanisms linking physiological aging to tumor progression remain unclear. Although age-related accumulation of genetic mutations contributes to tumorigenesis, increasing evidence indicates that the aging tissue microenvironment also plays a critical role in shaping cancer susceptibility. In this study, we integrated single-cell RNA sequencing and spatial transcriptomic datasets from healthy human skin and major skin cancers, including melanoma, squamous cell carcinoma, and basal cell carcinoma, to define cell-type-specific aging programs and assess their representation in tumor-associated microenvironments. In healthy skin, aging was associated with widespread but cell-type-specific transcriptional remodeling across epithelial, immune, vascular, and stromal compartments, involving pathways related to inflammation, extracellular matrix organization, and intercellular communication. Projection of these aging signatures into skin cancer datasets revealed that aging-associated programs were not restricted to immune cells but were also prominent in stromal compartments. Age-adjusted survival analysis in melanoma further identified the fibroblast aging program as the most prominent stromal signature, with higher program activity being associated with poor patient outcomes, motivating a focused analysis of fibroblast remodeling in skin cancers. Within this fibroblast-centered framework, we found that SFRP2-expressing fibroblasts accumulated in aged skin and were also enriched in tumor-associated stroma, suggesting that this pre-existing fibroblast state may become incorporated into and potentially support the tumor microenvironment during skin cancer development. Spatial analyses in basal cell carcinoma and squamous cell carcinoma showed that SFRP2-associated fibroblast signals were enriched near tumor-associated regions and WNT-active niches. Additional spatial proxy analyses and expression profiling of matrix-remodeling and growth factor-related genes further supported the association of this fibroblast state with tumor-associated stromal remodeling. Together, our findings suggest that aging-associated fibroblast remodeling may contribute to a tumor-permissive skin microenvironment and provide a framework for understanding how aging tissue ecosystems influence skin cancer progression.