Development of new preclinical models to advance adrenocortical carcinoma research
Development of new preclinical models to advance adrenocortical carcinoma research
复制标题
DOI：
10.1530/erc-17-0447
复制
发表时间：
2018-04-01
影响因子：
3.9
通讯作者：
Wierman, Margaret E.
中科院分区：
文献类型：
--
作者：
Kiseljak-Vassiliades, Katja;Zhang, Yu;Wierman, Margaret E.
肾上腺皮质癌（ACC）是一种罕见的恶性肿瘤，导致异质性的临床表型和分子基因型。对于这种致命的癌症，没有治愈性治疗方法，五年生存率为35%。由于缺乏临床前模型，我们对潜在病理生物学的理解和我们测试新治疗靶点的能力受到限制。在这里，我们报告了两个新的ACC细胞系和相应的患者来源的异种移植（PDX）模型的建立。CU-ACC 1细胞系和PDX来源于原发肿瘤分泌醛固酮的患者的肾周转移。CU-ACC 2细胞系和PDX来源于Lynch综合征患者的肝转移。短串联重复序列分析证实了人类样本和模型之间的一致匹配。对患者样品和模型进行外显子组和RNA测序分析，并在新细胞系中评价激素分泌。RNA测序和免疫组织化学证实了肾上腺皮质标记物在PDX和人类肿瘤中的表达。新的细胞系复制了两种已知的ACC遗传模型。CU-ACC 1细胞在CTNNB 1中有突变，分泌皮质醇，但不分泌醛固酮。CU-ACC 2细胞具有TP 53突变和MSH 2缺失，这与患者已知的导致林奇综合征的生殖系突变一致。两种细胞系都可以以相似的生长速率转染和转导。这些新的ACC临床前模型通过允许研究ACC的潜在分子机制和测试患者特异性治疗靶点的能力来显著推进该领域。
Adrenocortical cancer (ACC) is an orphan malignancy that results in heterogeneous clinical phenotypes and molecular genotypes. There are no curative treatments for this deadly cancer with 35% survival at five years. Our understanding of the underlying pathobiology and our ability to test novel therapeutic targets has been limited due to the lack of preclinical models. Here, we report the establishment of two new ACC cell lines and corresponding patient-derived xenograft (PDX) models. CU-ACC1 cell line and PDX were derived from a perinephric metastasis in a patient whose primary tumor secreted aldosterone. CU-ACC2 cell line and PDX were derived from a liver metastasis in a patient with Lynch syndrome. Short tandem repeat profiling confirmed consistent matches between human samples and models. Both exomic and RNA sequencing profiling were performed on the patient samples and the models, and hormonal secretion was evaluated in the new cell lines. RNA sequencing and immunohistochemistry confirmed the expression of adrenal cortex markers in the PDXs and human tumors. The new cell lines replicate two of the known genetic models of ACC. CU-ACC1 cells had a mutation in CTNNB1 and secreted cortisol but not aldosterone. CU-ACC2 cells had a TP53 mutation and loss of MSH2 consistent with the patient's known germline mutation causing Lynch syndrome. Both cell lines can be transfected and transduced with similar growth rates. These new preclinical models of ACC significantly advance the field by allowing investigation of underlying molecular mechanisms of ACC and the ability to test patient-specific therapeutic targets.