Babu Swathy, Chen Jiajia, Baron Chloé S, Sun Kaiwen, Robitschek Emily, McConnell Alicia M, Wu Constance, Dedeilia Aikaterini, Sade-Feldman Moshe, Modhurima Rodsy, Manos Michael P, Chen Kevin Y, Cox Anna M, Ludwig Calvin G, Kellis Manolis, Buchbinder Elizabeth I, Hacohen Nir, Yang Jiekun, Boland Genevieve M, Abraham Brian J, Liu David, Zon Leonard I, Insco Megan L
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital, Howard Hughes Medical Institute, Boston, MA, USA.
Nat Commun. 2025 Jul 22;16(1):6750. doi: 10.1038/s41467-025-61937-1.
Mucosal melanoma (MM) is a deadly cancer derived from mucosal melanocytes. To test the consequences of MM genetics, we develop a zebrafish model in which all melanocytes experience CCND1 expression and loss of PTEN and TP53. Surprisingly, melanoma only develops from melanocytes lining internal organs, analogous to the location of patient MM. We find that zebrafish MMs have a unique chromatin landscape from cutaneous melanomas. Internal melanocytes are labeled using a MM-specific transcriptional enhancer. Normal zebrafish internal melanocytes share a gene expression signature with MMs. Patient and zebrafish MMs show increased migratory neural crest and decreased antigen presentation gene expression, consistent with the increased metastatic behavior and decreased immunotherapy sensitivity of MM. Our work suggests that the cell state of the originating melanocyte influences the behavior of derived melanomas. Our animal model phenotypically and transcriptionally mimics patient tumors, allowing this model to be used for MM therapeutic discovery. As this is a non-MAPK driven genetically engineered model of melanoma, our work also has implications for the 15% of cutaneous melanoma patients who lack MAPK-driving mutations.
黏膜黑色素瘤（MM）是一种源自黏膜黑素细胞的致命癌症。为了测试MM遗传学的后果，我们开发了一种斑马鱼模型，其中所有黑素细胞都经历CCND1表达以及PTEN和TP53缺失。令人惊讶的是，黑色素瘤仅从内脏内衬的黑素细胞发展而来，类似于患者MM的发病部位。我们发现斑马鱼MM具有与皮肤黑色素瘤独特的染色质景观。使用MM特异性转录增强子标记内部黑素细胞。正常斑马鱼内部黑素细胞与MM具有共同的基因表达特征。患者和斑马鱼MM显示迁移性神经嵴增加，抗原呈递基因表达减少，这与MM转移行为增加和免疫治疗敏感性降低一致。我们的研究表明，起源黑素细胞的细胞状态会影响衍生黑色素瘤的行为。我们的动物模型在表型和转录水平上模拟患者肿瘤，使该模型可用于MM治疗发现。由于这是一种非MAPK驱动的黑色素瘤基因工程模型，我们的研究对15%缺乏MAPK驱动突变的皮肤黑色素瘤患者也有启示意义。
