Department of Dermatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
Department of Dermatology and Venereology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
Br J Dermatol. 2024 Oct 17;191(5):775-790. doi: 10.1093/bjd/ljae258.
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.
To characterize the stroma of the different BCC subtypes with a focus on CAF populations.
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.
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.
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.
基底细胞癌（BCC）是最常见的皮肤癌，也是人类最常见的恶性肿瘤。BCC 的不同形态亚型与低复发风险和侵袭性或高复发风险和侵袭性相关，但个体亚型产生的潜在生物学机制在很大程度上仍是未知的。由于大多数 BCC 似乎是由同一途径的突变引起的，我们假设 BCC 的发展、生长和侵袭潜能也受到肿瘤微环境的影响，特别是受到癌症相关成纤维细胞（CAF）及其分泌的因子的影响。
以 CAF 群体为重点，对不同 BCC 亚型的基质进行特征描述。
为了研究不同 BCC 亚型的基质特征，我们使用了激光捕获显微切割（LCM）和 RNA 测序（RNA-Seq）。从五个不同的“纯”亚型（即浅表型、结节型、微结节型、硬化型和基底鳞状型；各 3 例）中选择了 15 例 BCC 样本进行分析，并纳入了分析。健康皮肤作为对照（n=6）。结果通过免疫组织化学（IHC）进行了验证。我们在两个独立的公共单细胞 RNA-Seq（scRNA-Seq）数据集和 RNAscope 中验证了我们的发现。
不同 BCC 亚型的基质被发现具有不同的基因表达特征。结节型和微结节型似乎具有最相似的特征，而浅表型和硬化型则具有最不同的特征。通过比较低风险和高风险 BCC 亚型，我们发现 COL10A1 在硬化型/浸润型和基底鳞状型 BCC 的基质中过度表达，但在微结节型高风险亚型中则没有。这些发现通过 93 例不同的 BCC 和 13 例健康皮肤样本的 IHC 得到了证实。此外，来自两个独立数据集的 BCC 的 scRNA-Seq 分析发现，表达 COL10A1 的细胞群与浸润性 BCC 相邻的基质有关，并显示出细胞外基质重塑的特征。
我们将 COL10A1 鉴定为高危 BCC 的标志物，特别是硬化型/浸润型和基底鳞状型 BCC。我们在单细胞水平上证明，COL10A1 由浸润性 BCC 基质中与特定 CAF 群体相关的特定 CAF 群体表达。这为新的、量身定制的治疗方案开辟了道路，并提示 COL10A1 是 BCC 进展的新预后生物标志物。
