文章目录

APOBEC3A驱动脱氨酶结构域非依赖性染色体不稳定性促进胰腺癌转移

原文发布日期：2021-11-18

英文摘要：

摘要翻译：

原文链接：

文章：

APOBEC3A驱动脱氨酶结构域非依赖性染色体不稳定性促进胰腺癌转移

APOBEC3A drives deaminase domain-independent chromosomal instability to promote pancreatic cancer metastasis

原文发布日期：2021-11-18

英文摘要：

Despite efforts in understanding its underlying mechanisms, the etiology of chromosomal instability (CIN) remains unclear for many tumor types. Here, we identify CIN initiation as a previously undescribed function for APOBEC3A (A3A), a cytidine deaminase upregulated across cancer types. Using genetic mouse models of pancreatic ductal adenocarcinoma (PDA) and genomics analyses in human tumor cells we show that A3A-induced CIN leads to aggressive tumors characterized by enhanced early dissemination and metastasis in a STING-dependent manner and independently of the canonical deaminase functions of A3A. We show that A3A upregulation recapitulates numerous copy number alterations commonly observed in patients with PDA, including co-deletions in DNA repair pathway genes, which in turn render these tumors susceptible to poly (ADP-ribose) polymerase inhibition. Overall, our results demonstrate that A3A plays an unexpected role in PDA as a specific driver of CIN, with significant effects on disease progression and treatment.

摘要翻译：

尽管在阐明其基础机制方面付出了努力，许多肿瘤类型中染色体不稳定性（CIN）的病因仍然不清楚。在这里，我们发现CIN的启动是一个以前未描述的功能，由APOBEC3A（A3A）——一种在多种癌症类型中上调表达的胞嘧啶脱氧核苷酸水解酶驱动。通过使用胰腺管状腺癌（PDA）遗传小鼠模型和人类肿瘤细胞组学分析，我们证明了A3A诱导的CIN导致具有增强早期转移特性的侵袭性肿瘤，并以依赖STING的方式以及独立于APOBEC3A典型去磷酸化功能的形式驱动这种侵袭性。我们还表明，A3A上调 recapitulates（复现）了许多在PDA患者中常见的染色体数目变化，包括 DNA 修复通路基因的共缺失事件，这些肿瘤因此对多聚（ADP-ribose）聚合酶抑制剂易感。总之，我们的结果表明，A3A作为特定驱动CIN的 PDA 中的异常角色，对疾病进展和治疗具有显著影响。