ATM-deficiency increases genomic instability and metastatic potential in a mouse model of pancreatic cancer

Yiannis Drosos, David Escobar, Ming Yi Chiang, Kathryn Roys, Virginia Valentine, Marc B. Valentine, Jerold E. Rehg, Vaibhav Sahai, Lesa A. Begley, Jianming Ye, Leena Paul, Peter J. McKinnon, Beatriz Sosa-Pineda*

*Corresponding author for this work

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

Germline mutations in ATM (encoding the DNA-damage signaling kinase, ataxia-telangiectasia-mutated) increase Familial Pancreatic Cancer (FPC) susceptibility, and ATM somatic mutations have been identified in resected human pancreatic tumors. Here we investigated how Atm contributes to pancreatic cancer by deleting this gene in a murine model of the disease expressing oncogenic Kras (KrasG12D). We show that partial or total ATM deficiency cooperates with KrasG12D to promote highly metastatic pancreatic cancer. We also reveal that ATM is activated in pancreatic precancerous lesions in the context of DNA damage and cell proliferation, and demonstrate that ATM deficiency leads to persistent DNA damage in both precancerous lesions and primary tumors. Using low passage cultures from primary tumors and liver metastases we show that ATM loss accelerates Kras-induced carcinogenesis without conferring a specific phenotype to pancreatic tumors or changing the status of the tumor suppressors p53, p16Ink4a and p19Arf. However, ATM deficiency markedly increases the proportion of chromosomal alterations in pancreatic primary tumors and liver metastases. More importantly, ATM deficiency also renders murine pancreatic tumors highly sensitive to radiation. These and other findings in our study conclusively establish that ATM activity poses a major barrier to oncogenic transformation in the pancreas via maintaining genomic stability.

Original languageEnglish (US)
Article number11144
JournalScientific reports
Volume7
Issue number1
DOIs
StatePublished - Dec 1 2017

ASJC Scopus subject areas

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    Drosos, Y., Escobar, D., Chiang, M. Y., Roys, K., Valentine, V., Valentine, M. B., Rehg, J. E., Sahai, V., Begley, L. A., Ye, J., Paul, L., McKinnon, P. J., & Sosa-Pineda, B. (2017). ATM-deficiency increases genomic instability and metastatic potential in a mouse model of pancreatic cancer. Scientific reports, 7(1), [11144]. https://doi.org/10.1038/s41598-017-11661-8