Multi-omics analysis unveils the role of cancer-associated fibroblasts in cutaneous squamous cell carcinoma

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BACKGROUND: Human papillomavirus (HPV) infection is associated with an increased risk of cutaneous squamous cell carcinoma (CSCC). A comprehensive understanding of the cellular heterogeneity of HPV-positive and -negative CSCC is crucial for improving diagnosis and preventing tumor progression. METHODS: We conducted an integrated analysis of single-cell RNA and spatial transcriptomic data from different skin tissue sources to map the cellular landscape of the tumor microenvironment (TME) in both HPV positive and negative CSCC. Results were validated through multiplex immunohistochemistry (mIHC) and in vitro experiments. RESULTS: We identified 10 major cell types in CSCC and normal skin samples, including epithelial cells, myeloid cells, T cells, fibroblasts, endothelial cells, B cells, smooth muscle cells, mast cells, melanocytes, and hair follicle cells. Notably, fibroblasts were found to be associated with tumor progression in CSCC with or without HPV infected. We further identified eight major CAF subtypes in CSCC, with iCAFs-CXCL2 promoting tumor progression, while iCAFs-PLA2G2A acted to suppress tumor growth. The MDK-ITGA6 pair was found to mediate interactions between fibroblasts and epithelial cells in CSCC. mIHC analysis confirmed elevated expression of MDK and ITGA6 in CSCC samples. Additionally, cell co-culture experiments confirmed that MDK-mediated CAFs were shown to enhance tumor cell migration and invasion in CSCC. CONCLUSION: Our findings provide a comprehensive cellular atlas of CSCC, highlighting the association of CAFs in HPV infection and tumor progression of CSCC. These results also offer potential diagnostic and prognostic biomarkers for CSCC patients.

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