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

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

doi:10.1038/s41598-017-11661-8

Yiannis Drosos, Kathryn Roys + Show 11 more

Open Access

https://doi.org/10.1038/s41598-017-11661-8

Copy DOI

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.

Highlights

Germline mutations in ATM increase Familial Pancreatic Cancer (FPC) susceptibility, and ATM somatic mutations have been identified in resected human pancreatic tumors
Mice of the 3 genotypes were used in a survival study that was assembled to investigate the effects of ATM deficiency in KrasG12D-driven pancreatic tumor formation
Results of post-mortem analysis identified pancreatic tumors in 62% of KCATMΔ+ mice and in nearly 100% of KCATMΔΔ mice (Fig. 1A). This analysis uncovered liver metastases in 62% of KCATMΔ+ mice and in 78% of KCATMΔΔ mice (Fig. 1A). These data demonstrate that ATM deficiency synergizes with KrasG12D to promote the formation of highly metastatic pancreatic tumors

Summary

Introduction

Germline mutations in ATM (encoding the DNA-damage signaling kinase, ataxia-telangiectasiamutated) increase Familial Pancreatic Cancer (FPC) susceptibility, and ATM somatic mutations have been identified in resected human pancreatic tumors. ATM deficiency 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. Deep-sequencing methods identified deleterious mutations in ATM in human pancreatic tumors classified as ‘genetically unstable’[12] These and other results postulate that ATM activity poses a barrier to pancreatic cancer progression via maintaining chromosome stability. To test this hypothesis, we deleted Atm in pancreatic progenitors of the PDAC mouse model LSL-KrasG12D;Ptf1a+/cre ( known as KC)[13]

Methods

Results

Conclusion