| Literature DB >> 35121902 |
Sonja M Wörmann1,2, Amy Zhang3, Fredrik I Thege4,5, Robert W Cowan4,6, Dhwani N Rupani4,6, Runsheng Wang4,6, Sara L Manning4,6, Chris Gates7, Weisheng Wu7, Rena Levin-Klein8,9,10, Kimal I Rajapakshe4, Meifang Yu11, Asha S Multani12, Ya'an Kang13, Cullen M Taniguchi11, Katharina Schlacher14, Melena D Bellin15, Matthew H G Katz13, Michael P Kim13, Jason B Fleming16, Steven Gallinger3, Ravikanth Maddipati17, Reuben S Harris8,9,10,18, Faiyaz Notta3, Susan R Ross19,20, Anirban Maitra4,5, Andrew D Rhim21,22.
Abstract
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.Entities:
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Year: 2021 PMID： 35121902 DOI： 10.1038/s43018-021-00268-8
Source DB: PubMed Journal: Nat Cancer ISSN： 2662-1347