Background: Basal cell carcinoma (BCC) is the most frequently diagnosed skin cancer and the most common malignancy in humans. Different morphological subtypes of BCC are associated with a low or high risk of recurrence and aggressiveness, but the underlying biology of how the individual subtypes arise remains largely unknown. As the majority of BCCs appear to arise from mutations in the same pathway, we hypothesized that BCC development, growth and invasive potential is also influenced by the tumour microenvironment and, in particular, by cancer-associated fibroblasts (CAFs) and the factors they secrete.
Objectives: To characterize the stroma of the different BCC subtypes with a focus on CAF populations.
Methods: To investigate the stromal features of the different BCC subtypes, we used laser capture microdissection (LCM) followed by RNA sequencing (RNA-Seq). Fifteen BCC samples from five different 'pure' subtypes (i.e. superficial, nodular, micronodular, sclerosing and basosquamous; n = 3 each) were selected and included in the analysis. Healthy skin was used as a control (n = 6). The results were confirmed by immunohistochemistry (IHC). We validated our findings in two independent public single-cell RNA-Seq (scRNA-Seq) datasets and by RNAscope.
Results: The stroma of the different BCC subtypes were found to have distinct gene expression signatures. Nodular and micronodular appeared to have the most similar signatures, while superficial and sclerosing the most different. By comparing low- and high-risk BCC subtypes, we found that COL10A1 is overexpressed in the stroma of sclerosing/infiltrative and basosquamous but not in micronodular high-risk subtypes. Those findings were confirmed by IHC in 93 different BCC and 13 healthy skin samples. Moreover, scRNA-Seq analysis of BCCs from two independent datasets found that the COL10A1-expressing population of cells is associated with the stroma adjacent to infiltrative BCC and shows extracellular matrix remodelling features.
Conclusions: We identified COL10A1 as a marker of high-risk BCC, in particular of the sclerosing/infiltrative and basosquamous subtypes. We demonstrated at the single-cell level that COL10A1 is expressed by a specific CAF population associated with the stroma of infiltrative BCC. This opens up new, tailored treatment options, and suggests COL10A1 as a new prognostic biomarker for BCC progression.
Basal cell carcinoma (‘BCC’ for short) is the most common type of cancer in humans. BCC occurs when a certain type of skin cell transforms in the outermost layer of the skin. This is mostly caused by a lot of exposure to sunlight. BCC can appear in different forms, or ‘subtypes’. In each subtype, cancer cells grow in a specific way and are visually distinct from the surrounding tissue, known as the ‘stroma’. The different subtypes of BCC can have a low or high risk of cancer recurrence and different levels of aggressiveness. We aimed to find out what the stroma is made up of in the different subtypes of BCC, focusing on the differences between low-risk and high-risk cancers. We measured gene expression in specific areas of tissue and identified one gene called ‘COL10A1’ as being overexpressed in the stroma of high-risk BCC, especially in two particular subtypes (‘sclerosing’ and ‘basosquamous’ BCC). We confirmed this result in BCC biopsies. We also checked other published data and found that COL10A1 is mostly expressed in a type of cell called a ‘fibroblast’. Fibroblasts expressing the COL10A1 gene are present in the stroma right beside the infiltrative area of BCC. Our findings could be used to develop more personalized treatment of BCC. The stroma may be a potential anti-cancer target, as well as a new way of testing for BCC progression.
© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists.