Candidate therapeutic agents in a newly established triple wild-type mucosal melanoma cell line.
Candidate therapeutic agents in a newly established triple wild-type mucosal melanoma cell line.
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新建立的三重野生型粘膜黑色素瘤细胞系的候选治疗药物。
DOI：
10.1002/cac2.12315
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发表时间：
2022-07
影响因子：
16.2
通讯作者：
Zhou, Rong
中科院分区：
文献类型：
--
作者：
Shi, Chaoji;Gu, Ziyue;Xu, Shengming;Ju, Houyu;Wu, Yunteng;Han, Yong;Li, Jiayi;Li, Chuwen;Wu, Jing;Wang, Lizhen;Li, Jiang;Zhou, Guoyu;Ye, Weimin;Ren, Guoxin;Zhang, Zhiyuan;Zhou, Rong
关键词：
粘膜黑色素瘤具有独特的遗传特征和典型的不良预后。缺乏代表性的粘膜黑色素瘤模型，特别是细胞系，阻碍了对这种黑色素瘤亚型的转化研究。在本研究中，我们旨在建立并提供粘膜黑色素瘤细胞系的生物学特性、基因组特征和药理学特征，这将有助于理解和优化分子定义的粘膜黑色素瘤亚型的治疗。从一名67岁的粘膜黑色素瘤患者中采集样本，并将其加工成碎片，用于建立细胞系和患者源性异种移植物（PDX）模型。评价不同代次癌细胞的增殖和致瘤性，并对原始肿瘤、PDX、已建立的细胞系和匹配血液进行全基因组测序（WGS），以确认该细胞系的建立并确定其基因组特征。进行AmpliconArchitect以描绘通过WGS检测的扩增区域的结构。在已建立的细胞系上实施了包括总共103种治疗剂的高通量药物筛选（HTDS）测定，并在相应的PDX模型中验证了所选择的候选药物。建立了粘膜黑素瘤细胞系MM 9 H-1，其在超过100次连续传代后表现出稳健的增殖和致瘤性。MM 9 H-1、相应的PDX和原始肿瘤的基因组分析显示了基因组间的遗传保真度，MM 9 H-1被定义为缺乏充分表征的“驱动突变”的三重野生型（TWT）黑色素瘤亚型。相反，通过大规模基因组重排，几种癌基因的扩增，端粒酶逆转录酶（TERT），v-Raf小鼠肉瘤病毒癌基因同源物B1（BRAF），黑素细胞诱导转录因子（MITF）和INO 80复合物ATP酶亚基（INO 80）可能导致MM 9 H-1的肿瘤发生。此外，HTDS确定了蛋白酶体抑制剂，特别是硼替佐米，作为MM 9 H-1的有希望的治疗候选物，这在相应的体内PDX模型中得到了验证。我们建立并表征了一种新的粘膜黑色素瘤细胞系MM 9 H-1，并将该细胞系定义为缺乏充分表征的“驱动突变”的TWT黑色素瘤亚型。MM 9 H-1细胞系可作为粘膜黑色素瘤临床前研究的独特模型。
Mucosal melanoma has characteristically distinct genetic features and typically poor prognosis. The lack of representative mucosal melanoma models, especially cell lines, has hindered translational research on this melanoma subtype. In this study, we aimed to establish and provide the biological properties, genomic features and the pharmacological profiles of a mucosal melanoma cell line that would contribute to the understanding and treatment optimization of molecularly‐defined mucosal melanoma subtype. The sample was collected from a 67‐year‐old mucosal melanoma patient and processed into pieces for the establishment of cell line and patient‐derived xenograft (PDX) model. The proliferation and tumorigenic property of cancer cells from different passages were evaluated, and whole‐genome sequencing (WGS) was performed on the original tumor, PDX, established cell line, and the matched blood to confirm the establishment and define the genomic features of this cell line. AmpliconArchitect was conducted to depict the architecture of amplified regions detected by WGS. High‐throughput drug screening (HTDS) assay including a total of 103 therapeutic agents was implemented on the established cell line, and selected candidate agents were validated in the corresponding PDX model. A mucosal melanoma cell line, MM9H‐1, was established which exhibited robust proliferation and tumorigenicity after more than 100 serial passages. Genomic analysis of MM9H‐1, corresponding PDX, and the original tumor showed genetic fidelity across genomes, and MM9H‐1 was defined as a triple wild‐type (TWT) melanoma subtype lacking well‐characterized “driver mutations”. Instead, the amplification of several oncogenes, telomerase reverse transcriptase (TERT), v‐Raf murine sarcoma viral oncogene homolog B1 (BRAF), melanocyte Inducing transcription factor (MITF) and INO80 complex ATPase subunit (INO80), via large‐scale genomic rearrangement potentially contributed to oncogenesis of MM9H‐1. Moreover, HTDS identified proteasome inhibitors, especially bortezomib, as promising therapeutic candidates for MM9H‐1, which was verified in the corresponding PDX model in vivo. We established and characterized a new mucosal melanoma cell line, MM9H‐1, and defined this cell line as a TWT melanoma subtype lacking well‐characterized “driver mutations”. The MM9H‐1 cell line could be adopted as a unique model for the preclinical investigation of mucosal melanoma.
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影响因子：
82.9
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影响因子：
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通讯作者：
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通讯作者：
Guo J