Pleomorphic adenoma (PA) is the most common benign tumour in the salivary gland and has high morphological complexity. However, the origin and intratumoral heterogeneity of PA are largely unknown. Here, we constructed a comprehensive atlas of PA at single-cell resolution and showed that PA exhibited five tumour subpopulations, three recapitulating the epithelial states of the normal parotid gland, and two PA-specific epithelial cell (PASE) populations unique to tumours. Then, six subgroups of PASE cells were identified, which varied in epithelium, bone, immune, metabolism, stemness and cell cycle signatures. Moreover, we revealed that CD36⁺ myoepithelial cells were the tumour-initiating cells (TICs) in PA, and were dominated by the PI3K-AKT pathway. Targeting the PI3K-AKT pathway significantly inhibited CD36⁺ myoepithelial cell-derived tumour spheres and the growth of PA organoids. Our results provide new insights into the diversity and origin of PA, offering an important clinical implication for targeting the PI3K-AKT signalling pathway in PA treatment.

多形性腺瘤（PA）是唾液腺中最常见的良性肿瘤，具有高度的形态复杂性。然而，PA 的起源和瘤内异质性在很大程度上尚不清楚。在这里，我们构建了单细胞分辨率的 PA 综合图谱，并显示 PA 表现出五个肿瘤亚群，其中三个概括了正常腮腺的上皮状态，以及两个肿瘤特有的 PA 特异性上皮细胞 (PASE) 群。然后，鉴定出 PASE 细胞的六个亚群，它们在上皮、骨、免疫、代谢、干性和细胞周期特征方面各不相同。此外，我们发现 CD36 ⁺肌上皮细胞是 PA 中的肿瘤起始细胞（TIC），并且由 PI3K-AKT 通路主导。靶向 PI3K-AKT 通路显着抑制 CD36 ⁺肌上皮细胞衍生的肿瘤球和 PA 类器官的生长。我们的结果为 PA 的多样性和起源提供了新的见解，为 PA 治疗中靶向 PI3K-AKT 信号通路提供了重要的临床意义。