Integrated Single-Cell and Spatial Transcriptomic Analysis Reveals 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 mechanisms underlying this increased susceptibility remain incompletely understood. Traditionally, the accumulation of genetic mutations over time has been considered a primary driver of age-related tumorigenesis. However, emerging evidence highlights the critical role of the aging tissue microenvironment -- including changes in immune, stromal, and epithelial compartments -- in shaping cancer initiation and progression. In this study, we employed integrated single-cell and spatial transcriptomics to systematically characterize age-associated alterations in human skin and skin cancers. Our analysis uncovered widespread, cell type-specific transcriptional reprogramming with age, revealing key pathways and cellular populations that may contribute to a pro-tumorigenic environment. Notably, we identified a previously unrecognized fibroblast subtype marked by SFRP2 expression, which expands with age and is associated with poor prognosis in basal cell carcinoma. These fibroblasts appear to enhance Wnt signaling within the tumor niche, suggesting a potential mechanism by which the aging stroma supports malignancy. Collectively, our findings shed light on how age-related changes in tissue ecosystems may predispose to cancer and point to novel therapeutic opportunities for targeting the aged tumor microenvironment.