Squamous cell carcinoma (SCC) is a global public health burden originating in epidermal stem and progenitor cells (ESPCs) of the skin and mucosa. To understand how genetic risk factors contribute to SCC, studies of ESPC biology are imperative. Children with Fanconi anemia (FA) are a paradigm for extreme SCC susceptibility caused by germline loss-of-function mutations in FA DNA repair pathway genes. To discover epidermal vulnerabilities, patient-derived pluripotent stem cells (PSCs) conditional for the FA pathway were differentiated into ESPCs and PSC-derived epidermal organotypic rafts (PSC-EORs). FA PSC-EORs harbored diminished cell-cell junctions and increased proliferation in the basal cell compartment. Furthermore, desmosome and hemidesmosome defects were identified in the skin of FA patients, and these translated into accelerated blistering following mechanically induced stress. Together, we demonstrate that a critical DNA repair pathway maintains the structure and function of human skin and provide 3D epidermal models wherein SCC prevention can now be explored.

鳞状细胞癌（SCC）是一种全球公共卫生负担，起源于皮肤和粘膜的表皮干细胞和祖细胞（ESPC）。为了了解遗传风险因素如何导致鳞状细胞癌，对 ESPC 生物学的研究势在必行。患有范可尼贫血 (FA) 的儿童是 FA DNA 修复途径基因种系功能丧失突变引起的极度鳞状细胞癌易感性的一个范例。为了发现表皮的脆弱性，将 FA 途径有条件的患者来源的多能干细胞 (PSC) 分化为 ESPC 和 PSC 来源的表皮器官筏 (PSC-EOR)。FA PSC-EOR 的细胞间连接减少，基底细胞区室增殖增加。此外，在 FA 患者的皮肤中发现了桥粒和半桥粒缺陷，这些缺陷转化为机械诱导应力后加速起泡。我们共同证明了关键的 DNA 修复途径维持了人类皮肤的结构和功能，并提供了 3D 表皮模型，现在可以在其中探索 SCC 的预防。