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

Bibliographical note

Funding Information:
PKCY und A3AE PKCY mice when mice showed signs of sickness. Pancreata were washed in ice-cold PBS, minced and digested with 1.2mgml−1collagenase with protease inhibitor in advanced DMEM/F12, followed by red blood cell lysis (ACK buffer). YFP+ expressing cells were sorted directly into Buffer RLT Plus (with 2-mercaptoethanol) on the Aria Cell Sorter II (BD Bioscience) (flow cytometry and cellular imaging core facility partially funded by NCI Cancer Center Support Grant P30CA16672). DAPI was used to eliminate dead cells.

Funding Information:
We thank members of the Rhim laboratory for critical reading of the manuscript. S.M.W. is supported by the German Cancer Aid, Mildred-Scheel-Postdoctoral Fellow program. A.D.R. is supported by the V Foundation (V Scholar Grant), Doris Duke Foundation (Clinical Scholar Grant), Andrew Sabin Family Foundation, Cockrell Family Foundation, NCI (MD Anderson SPORE), MD Anderson Cancer Center (Physician Scientist Program, Pancreatic Cancer Moonshot) and CPRIT (Rising Stars Award). S.R.R. was supported by NIA (R21AG047114). Cancer studies in the Reuben Harris (R.S.H.) lab are supported by NCI P01 CA234228. R.L.K. received salary support from NIH T32 HL007062 and F32 CA232458. R.L.K. is an Awardee of the Weizmann Institute of Science–National Postdoctoral Award Program for Advancing Women in Science. R.S.H. is the Margaret Harvey Schering Land Grant Chair for Cancer Research, a Distinguished University McKnight Professor and an Investigator of the Howard Hughes Medical Institute. M.P.K. is supported by the NIH/NCI K08CA218690. Genomic instability analysis was done in the Cytogenetics and Cell Authentication Core (CCAC) at MD Anderson Cancer Center.

Funding Information:
Cell assays. Primary murine pancreatic tumor cell lines and liver metastasis cell lines were established from C57BL/6NJ backcrossed pancreatic murine tumors and liver metastasis. Only cultures below passage 10 were used. PDA patient-derived xenografts (hPDX) were obtained from MDA (Dr Fleming/Dr Kang). Xenografts were processed as previously described62,63 to establish low-passage primary PDA hPDX-derived in vitro cultures, and mouse cell contamination was eliminated through FACS for human HLA-A/B/C (antibody clone W6/32) on the Aria Cell Sorter II (BD Bioscience) (flow cytometry and cellular imaging core facility partially funded by NCI Cancer Center Support Grant P30CA16672). For proliferation and scratch assays, growth/wound closure was quantified using the Incucyte S3 device (Sartorius) and Incucyte S3 software (2019A). All reagents used are listed in Supplementary Table 10.

Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.

PubMed: MeSH publication types

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

Fingerprint

Dive into the research topics of 'APOBEC3A drives deaminase domain-independent chromosomal instability to promote pancreatic cancer metastasis'. Together they form a unique fingerprint.

Cite this