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

Sonja M. Wörmann, Amy Zhang, Fredrik I. Thege, Robert W. Cowan, Dhwani N. Rupani, Runsheng Wang, Sara L. Manning, Chris Gates, Weisheng Wu, Rena Levin-Klein, Kimal I. Rajapakshe, Meifang Yu, Asha S. Multani, Ya’an Kang, Cullen M. Taniguchi, Katharina Schlacher, Melena D. Bellin, Matthew H.G. Katz, Michael P. Kim, Jason B. FlemingSteven Gallinger, Ravikanth Maddipati, Reuben S. Harris, Faiyaz Notta, Susan R. Ross, Anirban Maitra, Andrew D. Rhim

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1338-1356
Number of pages19
JournalNature Cancer
Volume2
Issue number12
DOIs
StatePublished - Dec 2021
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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