Department of Oral and Maxillofacial-Head Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai 200011, China.
Sci Adv. 2023 Oct 27;9(43):eadg6686. doi: 10.1126/sciadv.adg6686.
Mucosal melanoma (MM), an aggressive rare subtype of melanoma, is distinct from cutaneous melanoma and has poor prognoses. We addressed the lack of cell models for MM by establishing 30 organoids of human oral MM (OMM), which retained major histopathological and functional features of parental tumors. Organoid groups derived from chronologically or intratumorally distinct lesions within the same individual displayed heterogeneous genetics, expression profiles, and drug responses, indicating rapid tumor evolution and poor clinical response. Furthermore, transcriptome analysis revealed receptor tyrosine kinases (RTKs) signaling, particularly , a nerve growth factor receptor, was significantly up-regulated in OMMs and organoids from patients resistant to anti-programmed cell death protein 1 (anti-PD-1) therapy. Combining anti-PD-1 with anlotinib (a phase 2 multitarget RTK inhibitor for OMM) or NGFR knockdown enhanced the effective activity of immune cells in organoid-immune cell coculture systems. Together, our study suggested that OMM organoids serve as faithful models for exploring tumor evolution and immunotherapy combination strategies.
黏膜黑色素瘤（MM）是一种侵袭性罕见的黑色素瘤亚型，与皮肤黑色素瘤不同，预后较差。我们通过建立 30 个人类口腔 MM（OMM）类器官来解决 MM 缺乏细胞模型的问题，这些类器官保留了亲本肿瘤的主要组织病理学和功能特征。源自同一患者中时间或肿瘤内不同病变的类器官群体表现出异质性的遗传、表达谱和药物反应，表明肿瘤快速进化和临床反应不佳。此外，转录组分析显示受体酪氨酸激酶（RTKs）信号，特别是神经生长因子受体（NGFR），在 OMM 和对抗程序性细胞死亡蛋白 1（抗 PD-1）治疗耐药的患者的类器官中显著上调。将抗 PD-1 与安罗替尼（一种用于 OMM 的 2 期多靶点 RTK 抑制剂）或 NGFR 敲低联合使用，增强了类器官-免疫细胞共培养系统中免疫细胞的有效活性。总之，我们的研究表明 OMM 类器官可作为探索肿瘤进化和免疫治疗联合策略的忠实模型。
