Management of thin melanomas (Breslow thickness <1mm) presents challenges due to the lack of adjuvant treatment options for this specific indication. Despite their favourable prognosis, 4% of thin melanoma cases remain at risk of metastatic dissemination and account for a quarter of all melanoma deaths due to the sheer volume of disease. While numerous studies have investigated the role of tumour infiltrating immune cells in melanoma progression, there is limited understanding of the functional phenotype of cancer-associated fibroblasts (CAFs) and their association with the invasiveness and metastatic potential of melanoma cells.
We employed spatial transcriptomics to analyse tumour sections from 15 fatal and 15 paired non-fatal cases of thin melanoma. This approach allowed us to decipher the spatial landscape of CAFs.
We annotated distinct CAF clusters and identified phenotypic differences of CAFs between fatal and non-fatal cases. Desmoplastic CAFs, which highly expressed extracellular matrix degradation-related genes, were more abundant in fatal cases. In contrast, inflammatory CAFs, enriched for immune regulatory genes, were more prevalent in non-fatal cases. We identified 65 genes that were significantly upregulated in CAFs from fatal cases, associated with ECM degradation, interferon signalling, and PDGF signalling, all of which promote epithelial-mesenchymal transition (EMT). Our findings indicate that CAFs from fatal cases exhibit unique phenotypes associated with modulating EMT-related processes, suggesting their role in promoting the invasiveness and metastatic potential of thin melanomas.
This study emphasizes the importance of studying stroma permissiveness by assessing the EMT propensity of CAFs in thin melanomas. It provides a novel strategy for early identification of high-risk patients and the early prevention of melanoma metastasis by targeting CAFs.