Lopes-Bastos Bruno, Nabais Joana, Ferreira Tânia, Allavena Giulia, El Maï Mounir, Bird Malia, Targen Seniye, Tattini Lorenzo, Kang Da, Yue Jia-Xing, Liti Gianni, Carvalho Tânia G, Godinho Ferreira Miguel
Institute for Research on Cancer and Aging of Nice (IRCAN), CNRS UMR7284, INSERM U1081, Université Côte d'Azur, 06107 Nice, France; Instituto Gulbenkian de Ciência, 2780-156 Oeiras, Portugal.
Instituto Gulbenkian de Ciência, 2780-156 Oeiras, Portugal.
Cell Rep. 2024 Dec 24;43(12):115035. doi: 10.1016/j.celrep.2024.115035. Epub 2024 Dec 4.
Most cancers re-activate telomerase to maintain telomere length and thus acquire immortality. Activating telomerase promoter mutations are found in many cancers, including melanoma. However, it is unclear when and if telomerase is strictly required during tumorigenesis. We combined the telomerase mutant (tert) with two established zebrafish melanoma models. We show that tert melanomas initially develop with similar incidence and invasiveness to tert tumors. However, they eventually decline in growth and regress. Late tert tumors exhibit reduced cell proliferation, increased apoptosis, and melanocyte differentiation. Notably, these tumors show enhanced immune cell infiltration and can resume growth when transplanted into immunocompromised hosts. We propose that telomerase is required for melanoma in zebrafish, albeit at later stages of progression, to sustain tumor growth while avoiding immune rejection and regression. Thus, the absence of telomerase restricts melanoma through tumor-autonomous mechanisms (cell-cycle arrest, apoptosis, and melanocyte differentiation) and a non-tumor-autonomous mechanism (immune rejection).
大多数癌症会重新激活端粒酶以维持端粒长度，从而获得永生。在包括黑色素瘤在内的许多癌症中都发现了激活端粒酶启动子的突变。然而，目前尚不清楚在肿瘤发生过程中端粒酶何时以及是否是严格必需的。我们将端粒酶突变体（tert）与两种已建立的斑马鱼黑色素瘤模型相结合。我们发现，tert黑色素瘤最初的发生频率和侵袭性与tert肿瘤相似。然而，它们最终生长减缓并消退。晚期tert肿瘤表现出细胞增殖减少、凋亡增加以及黑素细胞分化。值得注意的是，这些肿瘤显示出免疫细胞浸润增强，并且当移植到免疫受损宿主中时可以恢复生长。我们提出，尽管在进展的后期阶段，端粒酶对于斑马鱼黑色素瘤维持肿瘤生长同时避免免疫排斥和消退是必需的。因此，端粒酶的缺失通过肿瘤自主机制（细胞周期停滞、凋亡和黑素细胞分化）和非肿瘤自主机制（免疫排斥）来限制黑色素瘤。
