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

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. smwoermann@mdanderson.org.
² Department of Translational Molecular Pathology, MD Anderson Cancer Center, University of Texas, Houston, TX, USA. smwoermann@mdanderson.org.
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. arhim@mdanderson.org.
²² Department of Gastroenterology, Hepatology & Nutrition, MD Anderson Cancer Center, University of Texas, Houston, TX, USA. arhim@mdanderson.org.

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

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

Sonja M Wörmann et al. Nat Cancer. 2021 Dec.

. 2021 Dec;2(12):1338-1356.

doi: 10.1038/s43018-021-00268-8. Epub 2021 Nov 18.

Authors

Affiliations

¹ Ahmed Cancer Center for Pancreatic Cancer Research, MD Anderson Cancer Center, University of Texas, Houston, TX, USA. smwoermann@mdanderson.org.
² Department of Translational Molecular Pathology, MD Anderson Cancer Center, University of Texas, Houston, TX, USA. smwoermann@mdanderson.org.
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. arhim@mdanderson.org.
²² Department of Gastroenterology, Hepatology & Nutrition, MD Anderson Cancer Center, University of Texas, Houston, TX, USA. arhim@mdanderson.org.

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.

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Comment in

APOBEC3A drives STING-dependent metastasis.
Bakhoum SF. Bakhoum SF. Nat Cancer. 2021 Dec;2(12):1293-1295. doi: 10.1038/s43018-021-00286-6. Nat Cancer. 2021. PMID: 35121905 No abstract available.

References

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

Affiliations

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

Authors

Affiliations

Abstract

Comment in

References

Publication types

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Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Molecular Biology Databases

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