Ameloblastoma is a benign tumor characterized by locally invasive phenotypes, leading to facial bone destruction and a high recurrence rate. However, the mechanisms governing tumor initiation and recurrence are poorly understood. Here, we uncovered cellular landscapes and mechanisms that underlie tumor recurrence in ameloblastoma at single-cell resolution. Our results revealed that ameloblastoma exhibits five tumor subpopulations varying with respect to immune response (IR), bone remodeling (BR), tooth development (TD), epithelial development (ED), and cell cycle (CC) signatures. Of note, we found that CC ameloblastoma cells were endowed with stemness and contributed to tumor recurrence, which was dominated by the EZH2-mediated program. Targeting EZH2 effectively eliminated CC ameloblastoma cells and inhibited tumor growth in ameloblastoma patient-derived organoids. These data described the tumor subpopulation and clarified the identity, function, and regulatory mechanism of CC ameloblastoma cells, providing a potential therapeutic target for ameloblastoma.

成釉细胞瘤是一种良性肿瘤，其特征是局部侵袭性表型，导致面部骨质破坏和高复发率。然而，人们对控制肿瘤发生和复发的机制知之甚少。在这里，我们以单细胞分辨率揭示了成釉细胞瘤肿瘤复发的细胞景观和机制。我们的结果显示，成釉细胞瘤表现出五种在免疫反应（IR）、骨重塑（BR）、牙齿发育（TD）、上皮发育（ED）和细胞周期（CC）特征方面各不相同的肿瘤亚群。值得注意的是，我们发现CC成釉细胞瘤细胞被赋予干性并导致肿瘤复发，这是由EZH2介导的程序主导的。靶向 EZH2 可有效消除 CC 成釉细胞瘤细胞并抑制成釉细胞瘤患者来源的类器官中的肿瘤生长。这些数据描述了肿瘤亚群，并阐明了CC成釉细胞瘤细胞的身份、功能和调控机制，为成釉细胞瘤提供了潜在的治疗靶点。