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Chromosomal instability (CIN), a hallmark of cancer, has been associated with a highly metastatic phenotype in numerous cancers. Mechanisms by which these genomic events occur during the lifespan of a neoplasm have yet to be fully delineated. In our study we identified a novel function for APOBEC3A (A3A), a primate-specific cytidine deaminase upregulated in multiple cancers including Pancreatic ductal adenocarcinoma (PDAC), in the initiation of CIN.We demonstrate that A3A is not routinely detected in non-diseased pancreata; however, expression was detected in the epithelial and stromal compartments from patients with chronic pancreatitis and in precursor lesions of PDAC and is further significantly increased in invasive neoplasia. Strikingly, we found that A3A expression but not A3A-induced mutagenesis, was associated with a significantly reduced overall survival in PDAC. By employing a variety of genetic tools, we identified a novel function for A3A in initiating CIN, underscoring its potential role in driving the observed early metastatic propensity in PDAC. Using a series of in vivo and in vitro models, we demonstrate that A3A-induced CIN leads to aggressive cancer, featuring enhanced, STING-dependent, distant organ seeding and metastatic growth. As a consequence of aberrant A3A function and CIN-mediated upregulation of STING, NfkB and Stat3 pathways were activated. More importantly, all these effects were independent of the deaminase domain, underscoring a novel role of A3A beyond its established canonical function. Remarkably, in a novel autochthonous murine model of PDA expressing human A3A, we identified numerous copy number changes, homologous to those altered in A3A overexpressing patient tumors, including deletions in DNA repair pathway genes. While we showed that A3A-expressing PDAC cells do not fully phenocopy a BRCA mutation-like phenotype, A3A-expressing PDAC cells are exceptionally sensitive to PARP inhibition and DNA cross linking agents, recapitulating a state of “chemical BRCAness”. The combined effect of deletions in these genes has yet to be ascertained, and we hypothesize that these losses further add to ongoing DNA damage overall in PDAC. In summary, our study shows, that A3A drives metastasis and specific deletions through a deaminase-independent initiation of CIN, with potential implications for targeted treatment strategies in pancreatic cancer. Citation Format: Sonja Maria Woermann, Amy Zhang, Fredrik I. Thege, Chris Gates, Reuben S. Harris, Susan R. Ross, Faiyaz Notta, Anirban Maitra, Andrew D. Rhim. APOBEC3A a causative agent in cancer-related chromosomal instability and STING driven metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1506. |
