Ahmed Cancer Center for Pancreatic Cancer Research, MD Anderson Cancer Center, University of Texas, Houston, TX, USA.
Department of Translational Molecular Pathology, MD Anderson Cancer Center, University of Texas, Houston, TX, USA.
Nat Cancer. 2021 Dec;2(12):1338-1356. doi: 10.1038/s43018-021-00268-8. Epub 2021 Nov 18.
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.
尽管人们努力了解其潜在机制，但许多肿瘤类型的染色体不稳定性 (CIN) 的病因仍不清楚。在这里，我们将 CIN 的起始鉴定为 APOBEC3A（A3A）的一个以前未被描述的功能，A3A 是一种在多种癌症类型中上调的胞嘧啶脱氨酶。使用胰腺导管腺癌 (PDA) 的遗传小鼠模型和人类肿瘤细胞的基因组学分析，我们表明 A3A 诱导的 CIN 导致侵袭性肿瘤，其特征是通过 STING 依赖性方式和独立于 A3A 的经典脱氨酶功能进行早期扩散和转移增强。我们表明，A3A 的上调再现了许多在 PDA 患者中常见的拷贝数改变，包括 DNA 修复途径基因的共同缺失，这反过来又使这些肿瘤容易受到聚 (ADP-核糖) 聚合酶抑制的影响。总体而言，我们的研究结果表明，A3A 在 PDA 中作为 CIN 的特定驱动因素发挥了意想不到的作用，对疾病进展和治疗有重大影响。
