Journal
NATURE CANCER
Volume 2, Issue 12, Pages 1338-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s43018-021-00268-8
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Funding
- German Cancer Aid, Mildred-Scheel-Postdoctoral Fellow program
- V Foundation
- Doris Duke Foundation
- Andrew Sabin Family Foundation
- Cockrell Family Foundation
- NCI (MD Anderson SPORE)
- MD Anderson Cancer Center (Physician Scientist Program, Pancreatic Cancer Moonshot)
- CPRIT (Rising Stars Award)
- NIA [R21AG047114]
- NCI [P01 CA234228]
- NIH [T32 HL007062, F32 CA232458]
- Margaret Harvey Schering Land Grant Chair for Cancer Research
- NIH/NCI [K08CA218690]
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Researchers have discovered an unexpected role of APOBEC3A in inducing chromosomal instability and STING-dependent metastasis in human and mouse pancreatic cancer. Upregulation of A3A leads to aggressive tumors with early dissemination and metastasis characteristics, as well as increased susceptibility to poly (ADP-ribose) polymerase inhibition.
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. Woermann and colleagues describe a deaminase-independent function for APOBEC3A in initiating chromosomal instability and STING-dependent metastasis in human and mouse pancreatic cancer.
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