Building a Better Mouse Model for High-Grade Serous Carcinoma

Researchers at the University of Michigan have recently developed a genetically engineered mouse model (GEMM) of high-grade serous carcinoma (HGSC) that could prove useful in the preclinical testing of prevention strategies for ovarian cancer, as well as for other translational applications. HGSC is the most common and lethal type of ovarian cancer.

Details of this novel GEMM will be presented in a lecture titled, “Modeling the Genomics of High-Grade Serous Carcinoma in the Mouse,” on September 13 at the 12th Biennial Ovarian Cancer Research Symposium held in Seattle. 

“We made genetically engineered mice that model human HGSC, in which we manipulated certain tumor suppressor genes in the fallopian tube epithelium,” said presenter and principal investigator, Kathleen R. Cho, MD, the Peter A. Ward Professor of Pathology at the University of Michigan Medical School in Ann Arbor.

“The specific genes were picked because they are frequently altered in human HGSCs. When we inactivate these genes in the mouse oviduct [equivalent to the human fallopian tube], the mice develop cancers that are very similar to human HGSCs. They look similar under the microscope, they have a similar genetic basis, and they acquire gene expression profiles and additional genetic alterations that are similar to those observed in human HGSCs,” noted Cho.

Of note, HGSC is technically not an ovarian cancer at all, but rather a cancer that usually arises from epithelial cells in the fallopian tube.

Cho and colleagues employed the Cre-lox system to generate the genetically engineered mice. In the Cre-lox system, an enzyme called Cre recombinase is used to direct recombination of genes that have been engineered to contain specific recognition sequences called loxP sites. The Cre-lox system has been used previously by many other researchers to manipulate an ambit of genes responsible for various cancers, including Brca1 and Trp53, two of the engineered (“floxed”) genes included in the new mouse model of HGSC.

The investigators designed transgenic (Ovgp1-iCreER^T2) mice in which Cre recombinase expression is regulated by the promoter of a gene called Ovgp1 (oviductal glycoprotein 1) that is expressed almost exclusively in the oviductal epithelium. This step enables spatial control of where Cre recombinase is expressed. Furthermore, the Cre recombinase expression cassette that the investigators used allows Cre’s enzymatic function to be activated by tamoxifen. When Ovgp1-iCreER^T2 mice that also carry certain floxed tumor suppressor gene alleles are treated with tamoxifen, they develop HGSC-like oviductal tumors.   

“We have spatial control through the Ovgp1 promoter, and temporal control through tamoxifen treatment. And that’s how we can choose where and when these mice develop tumors,” said Cho.

Although other models have been developed for HGSC, Cho highlights some advantages to the GEMM developed in her lab.

First, in their model, once Cre is activated, it usually takes several months for full-blown tumors to develop. This long latency period likely allows for selection of additional genetic alterations in the mouse, similar to those seen in human cancers during neoplastic transformation. The long latency period also opens the door for analysis of ovarian cancer prevention strategies by providing a lengthy window of opportunity during which to interrupt or delay disease progression. 

Second, the GEMM is immunocompetent. Although many insights have been gained by studying the biology of human ovarian cancer cells transplanted into immunocompromised mice, such xenograft systems are suboptimal for studying potentially important interactions between the cancer cells and the immune system. 

On a final note, Cho reflects on the importance of mouse and other animal models-none of which are perfect but collectively provide researchers with useful tools for studying HGSC. 

“Robust animal models that closely recapitulate the cell of origin, genetics, and genomics of human HGSCs are expected to be very useful for preclinical studies aimed at testing novel ovarian cancer prevention, early detection, and therapeutic approaches.”