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Updated: Feb 23, 2026
A Preclinical Murine Model of Hepatic Metastases
Published on: September 27, 2014
ATM-deficiency increases genomic instability and metastatic potential in a mouse model of pancreatic cancer
Yiannis Drosos1, David Escobar2, Ming-Yi Chiang2
1Department of Genetics, St. Jude Children's Research Hospital, Memphis, TN, United States.
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.
Insights
ATM deficiency accelerates pancreatic cancer by promoting metastasis and genomic instability in a mouse model. This ATM loss makes pancreatic tumors more sensitive to radiation therapy, highlighting ATM
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Germline mutations in ATM (ataxia-telangiectasia-mutated) increase susceptibility to familial pancreatic cancer.
- ATM somatic mutations are found in human pancreatic tumors.
- ATM plays a crucial role in DNA damage signaling.
Purpose of the Study:
- To investigate the role of ATM in pancreatic cancer development using a genetically engineered mouse model.
- To determine how ATM deficiency affects Kras-driven pancreatic carcinogenesis and metastasis.
- To assess the impact of ATM loss on genomic stability and sensitivity to radiation therapy.
Main Methods:
- Deletion of the Atm gene in a mouse model expressing oncogenic Kras (KrasG12D).
- Analysis of pancreatic precancerous lesions, primary tumors, and liver metastases.
- Assessment of DNA damage, chromosomal alterations, and tumor suppressor gene status (p53, p16Ink4a, p19Arf).
- Evaluation of tumor sensitivity to radiation therapy.
Main Results:
- Partial or total ATM deficiency cooperated with KrasG12D to promote highly metastatic pancreatic cancer.
- ATM deficiency led to persistent DNA damage in precancerous lesions and tumors.
- ATM loss accelerated Kras-induced carcinogenesis without altering key tumor suppressor pathways.
- ATM deficiency significantly increased chromosomal alterations and rendered tumors sensitive to radiation.
Conclusions:
- ATM activity is a critical barrier to pancreatic oncogenesis by maintaining genomic stability.
- ATM deficiency promotes pancreatic cancer progression and metastasis.
- ATM-deficient pancreatic tumors exhibit increased sensitivity to radiation, suggesting therapeutic implications.
