In vivo modeling of metastatic human high-grade serous ovarian cancer in mice

Olga Kim ¹, Eun Young Park ¹, David L Klinkebiel ²

¹Department of Biochemistry and Molecular Biology, Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
²Department of Biochemistry and Molecular Biology, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
³Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
⁴Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
⁵Department of Pathology and Genomic Medicine, Houston Methodist and Weill Cornell Medical College, Houston, Texas, United States of America.
⁶Department of Pathology, School of Medicine, Keimyung University, Daegu, Republic of Korea.
⁷Department of Medicine, Baylor College of Medicine, Houston, Texas, United States of America.
⁸Research and Development Center, Bioway Inc, Seoul, Republic of Korea.
⁹Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, United States of America.
¹⁰Department of Obstetrics, Gynecology & Reproductive Sciences, Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
¹¹Department of Biochemistry and Molecular Medicine, University of California, Davis, Sacramento, California, United States of America.
¹²Department of Regenerative and Cancer Cell Biology, Albany Medical College, Albany, NY, United States of America.
¹³Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut, United States of America.
¹⁴Department of Surgery, Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
¹⁵Medical Sciences Program, Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Bloomington, Indiana, United States of America.
¹⁶Departments of Genetics, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
¹⁷School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia, United States of America.
¹⁸Department of Obstetrics and Gynecology, School of Medicine, Keimyung University, Daegu, Republic of Korea.
¹⁹Department of Cellular and Molecular Medicine, University of Ottawa, and Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
²⁰Penn Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
²¹Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
²²Department of Medicine, Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine Indianapolis, Indiana, United States of America.
²³Eppley Institute for Cancer Research, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.

⁰Department of Biochemistry and Molecular Biology, Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.

Plos Genetics +

|

June 5, 2020

View abstract on PubMed

Summary

Researchers developed a new mouse model for high-grade serous ovarian cancer (HGSC) metastasis. This model accurately replicates human HGSC peritoneal spread and associated mortality, aiding in understanding and treating this deadly cancer.

Area Of Science

Oncology
Genetics
Cancer Biology

Background

Metastasis causes 90% of cancer deaths.
Modeling human cancer metastasis in vivo remains a significant challenge.
High-grade serous ovarian cancer (HGSC) is the most common and lethal type of ovarian cancer.

Purpose Of The Study

To develop a robust mouse model for high-grade serous ovarian cancer (HGSC) metastasis.
To create a model that accurately recapitulates the peritoneal spread and mortality seen in human HGSC.
To provide a valuable tool for studying HGSC progression and evaluating therapeutic strategies.

Main Methods

Genetic engineering of mice to inactivate Dicer1 and Pten, and introduce mutant p53.
Observation and analysis of tumor development, metastasis patterns, and survival rates in engineered mice.
Histopathological and molecular/genomic characterization of mouse tumors.

Main Results

Engineered mice developed high-grade serous ovarian cancer (HGSC) with complete penetrance.
Tumors originated in the fallopian tube, spread to the ovary, and extensively colonized the peritoneal cavity, causing hemorrhagic ascites and 100% mortality.
Mouse HGSCs exhibited phenotypic, histopathological, chromosomal instability, impaired DNA repair, and chemosensitivity features similar to human HGSC.

Conclusions

The developed murine model faithfully recapitulates the clinical, molecular, and genomic features of human HGSC metastasis.
This model serves as a valuable preclinical tool for investigating HGSC pathogenesis.
The model will facilitate the evaluation of novel therapeutic interventions for metastatic ovarian cancer.

Related Concept Videos

Mouse Models of Cancer Study

Mice have long served as models for studying human biology and pathology because of their phylogenetic and physiological similarity with humans. They are also easy to maintain and breed in the laboratory, and hence, many inbred strains are now available for research. Studies on mice have contributed immeasurably to our understanding of cancer biology.
The development of transgenic, knockout, and knock-in mice has led to an exponential increase in their use as model organisms in research,...