Modeling High-grade serous ovarian carcinoma using a combination of in vivo electroporation and CRISPR/Cas9 mediated genome editing

Abstract

Ovarian cancer remains the most lethal gynecological cancer today. High-grade serous ovarian carcinoma (HGSC) is the most common and lethal type of ovarian cancer and is most frequently diagnosed at advanced stages. Here, we developed a novel strategy to generate somatic ovarian cancer mouse models using a combination of in vivo electroporation and CRISPR/Cas9 mediated genome editing. We mutated tumor suppressor genes associated with HGSC in two different combinations; Brca1, Tp53, Pten with/without Lkb1 and successfully generated HGSC, however, with different latencies and pathophysiology. By utilizing Cre lineage tracing in our system, we visualized peritoneal micrometastases in an immune-competent environment. Because our strategy is flexible in selecting mutation combinations and targeting areas, it would be useful for generating ovarian cancer mouse models. Significance StatementHigh grade serous ovarian cancer (HGSC) is the most common ovarian malignancy but our knowledge of early tumorigenesis is still quite limited due to late diagnosis of patients. We developed a new strategy of generating mouse ovarian cancer models using a combination of in vivo electroporation and CRISPR-mediated genome editing. We demonstrated that a combination of three tumor suppressor gene mutations (Brca1, Tp53 and Pten) is sufficient to develop HGSCs. Interesting, an additional mutation in Lkb1 drastically changed tumor latency, penetrance and pathophysiology through changing its cell-of-origin. Our strategy is highly flexible in selection of mutation combinations and targeting areas in immune competent mice and useful to study early tumorigenesis of ovarian cancer.