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 Fleming; Steven Gallinger; Ravikanth Maddipati; Reuben S Harris; Faiyaz Notta; Susan R Ross; Anirban Maitra; Andrew D Rhim

doi:10.1038/s43018-021-00268-8

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

Nat Cancer. 2021 Dec;2(12):1338-1356. doi: 10.1038/s43018-021-00268-8. Epub 2021 Nov 18.

Authors

Sonja M Wörmann^{1

2}, Amy Zhang³, Fredrik I Thege^{4

5}, Robert W Cowan^{4

6}, Dhwani N Rupani^{4

6}, Runsheng Wang^{4

6}, Sara L Manning^{4

6}, Chris Gates⁷, Weisheng Wu⁷, Rena Levin-Klein^{8

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 Harris^{8

9

10

18}, Faiyaz Notta³, Susan R Ross^{19

20}, Anirban Maitra^{4

5}, Andrew D Rhim^{21

22}

Affiliations

¹ Ahmed Cancer Center for Pancreatic Cancer Research, MD Anderson Cancer Center, University of Texas, Houston, TX, USA. [email protected].
² Department of Translational Molecular Pathology, MD Anderson Cancer Center, University of Texas, Houston, TX, USA. [email protected].
³ Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
⁴ Ahmed Cancer Center for Pancreatic Cancer Research, MD Anderson Cancer Center, University of Texas, Houston, TX, USA.
⁵ Department of Translational Molecular Pathology, MD Anderson Cancer Center, University of Texas, Houston, TX, USA.
⁶ Department of Gastroenterology, Hepatology & Nutrition, MD Anderson Cancer Center, University of Texas, Houston, TX, USA.
⁷ BRCF Bioinformatics Core, University of Michigan, School of Medicine, Ann Arbor, MI, USA.
⁸ Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA.
⁹ Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
¹⁰ Institute for Molecular Virology, University of Minnesota, Minneapolis, MN, USA.
¹¹ Department of Experimental Radiation Oncology, MD Anderson Cancer Center, University of Texas, Houston, TX, USA.
¹² Department of Genetics, MD Anderson Cancer Center, University of Texas, Houston, TX, USA.
¹³ Department of Surgical Oncology, MD Anderson Cancer Center, University of Texas, Houston, TX, USA.
¹⁴ Department of Cancer Biology, Division of Basic Science Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹⁵ University of Minnesota Medical Center, Schulze Diabetes Institute, Minneapolis, MN, USA.
¹⁶ Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA.
¹⁷ Department of Internal Medicine and Hamon Center for Therapeutic Oncology Research and Children's Research Institute, UT Southwestern Medical Center, Dallas, TX, USA.
¹⁸ Howard Hughes Medical Institute, University of Minnesota, Minneapolis, Minnesota, USA.
¹⁹ Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
²⁰ Department of Microbiology and Immunology, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
²¹ Ahmed Cancer Center for Pancreatic Cancer Research, MD Anderson Cancer Center, University of Texas, Houston, TX, USA. [email protected].
²² Department of Gastroenterology, Hepatology & Nutrition, MD Anderson Cancer Center, University of Texas, Houston, TX, USA. [email protected].

PMID: 35121902
DOI: 10.1038/s43018-021-00268-8

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.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Chromosomal Instability / genetics
Cytidine Deaminase* / genetics
Humans
Mice
Pancreatic Neoplasms* / genetics
Proteins / genetics

Substances

Proteins
APOBEC3A protein, human
Cytidine Deaminase

Abstract

Publication types

MeSH terms

Substances

Grants and funding