The Syrian Golden hamster (Mesocricetus auratus) is an emerging model organism for human diseases that complements current rodent models. It has been demonstrated to be especially effective in modeling human disorders such as diet-induced early atherosclerosis, inflammatory myopathies, emerging viral infectious diseases, Clostridium difficile infection, pancreatitis, diet-induced obesity, insulin resistance, lipid metabolism and virally and chemically-induced cancers. Moreover, as a designated high-priority animal model the hamster genome has recently been fully sequenced, along with a full description of the hamster transcriptome. However, until recently a significant challenge for the use of hamsters in modeling human diseases was the inability to generate genetically engineered hamsters. This barrier has recently been surmounted by our group resulting in gene knockouts in hamsters by employing CRISPR/Cas9-mediated gene targeting, piggyBac-mediated transgenesis and pronuclear injection. This permits the creation of the first genetic models of cancer in hamsters. One of the first genes that we investigated encodes for the KCNQ1 potassium channel. KCNQ1 mutations cause a range of pathologies in humans such as cardiac arrhythmia, inner ear defects and gastric hyperplasia and we have shown that deficiency for Kcnq1 enhances GI cancer phenotypes in mouse models and low expression of KCNQ1 is associated with poor prognosis in stage II, III, and IV colorectal cancer. We generated eight KCNQ1 homozygous KO hamsters that were aged and phenotyped. As early as 50 days of age six of the homozygous mutants started showing signs of distress and upon necropsy all of the hamsters had visible cancers (hemangiosarcomas, lymphomas, myeloid leukemias, multiple myelomas), often synchronous, very large and infiltrating multiple tissues, including liver, lung, pancreas and omentum, intestine, kidney, spleen, ovaries, sternum, lymph nodes, stomach in addition to systemic myeloid disease involving bone marrow, lung, liver and spleen. None of the hamsters in our colony that were wildtype or heterozygous for KCNQ1 mutations developed cancers indicating that the cancer phenotype is linked to KCNQ1-deficiency. The susceptibility or resistance of hamsters to genetically engineered cancers can inform on how these cancers may develop in humans, help clarify differences with genetic mouse and rat models of cancer, and may lead to new therapeutic interventions. To our knowledge, this study represents the creation of the first genetically engineered hamster cancer model. The challenge now is to characterize these cancers at the molecular level and discover altered genetic and biochemical pathways that give rise to them.

Public Health Relevance

The first genetically engineered Syrian Golden hamsters, deficient for the the KCNQ1 potassium channel, resulted in a novel cancer syndrome. This new animal model can inform on how these cancers develop in humans, clarify differences with other rodent models of cancer, and may lead to new therapeutic interventions.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Small Research Grants (R03)
Project #
1R03CA234201-01
Application #
9647929
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Jhappan, Chamelli
Project Start
2019-01-16
Project End
2020-12-31
Budget Start
2019-01-16
Budget End
2019-12-31
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455