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

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

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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 language	English (US)
Pages (from-to)	1338-1356
Number of pages	19
Journal	Nature Cancer
Volume	2
Issue number	12
DOIs	https://doi.org/10.1038/s43018-021-00268-8
State	Published - Dec 2021

ASJC Scopus subject areas

Oncology
Cancer Research

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Wörmann, S. M., Zhang, A., Thege, F. I., Cowan, R. W., Rupani, D. N., Wang, R., Manning, S. L., Gates, C., Wu, W., Levin-Klein, R., Rajapakshe, K. I., Yu, M., Multani, A. S., Kang, Y., Taniguchi, C. M., Schlacher, K., Bellin, M. D., Katz, M. H. G., Kim, M. P., ... Rhim, A. D. (2021). APOBEC3A drives deaminase domain-independent chromosomal instability to promote pancreatic cancer metastasis. Nature Cancer, 2(12), 1338-1356. https://doi.org/10.1038/s43018-021-00268-8

Wörmann, SM, Zhang, A, Thege, FI, Cowan, RW, Rupani, DN, Wang, R, Manning, SL, Gates, C, Wu, W, Levin-Klein, R, Rajapakshe, KI, Yu, M, Multani, AS, Kang, Y, Taniguchi, CM, Schlacher, K, Bellin, MD, Katz, MHG, Kim, MP, Fleming, JB, Gallinger, S, Maddipati, R, Harris, RS, Notta, F, Ross, SR, Maitra, A & Rhim, AD 2021, 'APOBEC3A drives deaminase domain-independent chromosomal instability to promote pancreatic cancer metastasis', Nature Cancer, vol. 2, no. 12, pp. 1338-1356. https://doi.org/10.1038/s43018-021-00268-8

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title = "APOBEC3A drives deaminase domain-independent chromosomal instability to promote pancreatic cancer metastasis",

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.",

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

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2021",

month = dec,

doi = "10.1038/s43018-021-00268-8",

language = "English (US)",

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AU - Wörmann, Sonja M.

AU - Zhang, Amy

AU - Thege, Fredrik I.

AU - Cowan, Robert W.

AU - Rupani, Dhwani N.

AU - Wang, Runsheng

AU - Manning, Sara L.

AU - Gates, Chris

AU - Wu, Weisheng

AU - Levin-Klein, Rena

AU - Rajapakshe, Kimal I.

AU - Yu, Meifang

AU - Multani, Asha S.

AU - Kang, Ya’an

AU - Taniguchi, Cullen M.

AU - Schlacher, Katharina

AU - Bellin, Melena D.

AU - Katz, Matthew H.G.

AU - Kim, Michael P.

AU - Fleming, Jason B.

AU - Gallinger, Steven

AU - Maddipati, Ravikanth

AU - Harris, Reuben S.

AU - Notta, Faiyaz

AU - Ross, Susan R.

AU - Maitra, Anirban

AU - Rhim, Andrew D.

PY - 2021/12

Y1 - 2021/12

N2 - 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.

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

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