Introduction: Ovarian epithelial tumors are highly heterogeneous. Patients are diagnosed late, when tumors have spread to the surrounding tissues, most often to the omentum. Despite optimal removal and response to therapy, the tumors often recur. Personalized medicine approaches often require molecular profiling of tumors, for patient selection and to predict response to therapy. Given intratumor heterogeneity, identification of tumor sites that are best to select for profiling is still up for debate.

Approach: We recently developed triple transgenic (MUC1KrasPten.Tg) mice that develop orthotopic MUC1-expressing endometrioid ovarian tumors. The tumors develop in the ovaries and spread throughout the peritoneal cavity, closely mirroring the human disease. Using tumor cells isolated from either the MUC1KrasPten primary ovarian tumor (MKP-T) or the liver implant (MKP-L), we generated several new murine ovarian cancer cell lines which express human MUC1 as self, while simultaneously carrying constitutively active oncogenic Kras and defective Pten tumor suppressor.

Results: MKP-T and MKP-L showed variable expression pattern of MUC1, EpCAM, folate receptor, ALDH, cytokeratin and vimentin, demonstrating the relationship between the anatomical location of each originating tumor and the cell line's in vitro phenotype. Unlike the MKP-L cells, the MKP-T cells display loss of K-ras heterozygosity, suggesting that migration to a metastatic site was an early event. Although both cell lines can grow IP tumors in syngeneic triple transgenic MUC1KrasPten.Tg, they carry distinct in vivo phenotypes. MKP-T cells multiply at higher rate and generate larger loco- regional tumors. In contrast, the MKP-L cells, derived from a metastatic site, have a slower growth rate but spread throughout the peritoneal cavity, undergo epithelial-mesenchymal transition (EMT) and trigger distant metastases to the lungs(MKP-Lng). In line with their Kras status, MEK 1/2 inhibitor AZD6244 (currently tested in several Phase II clinical trials) is more effective on MKP-T cells than on MKP-L and MKP-Lng cells in vitro, suggesting that metastatic tumor cells may be more resistant to MEK1/2 inhibitiors.

Conclusions: Using novel murine tumor cell populations, we reproduce intratumoral heterogeneity and demonstrate that in vitro and in vivo biological properties vary with the location of originating tumor. Most importantly, we show that cells derived from metastatic sites, which are more likely to reproduce the characteristic of the recurrent tumors, have an increased metastatic potential and reduced response to therapeutic drugs. These results suggest that molecular profiling of tumors needs to focus on multiple tumor sites and that in ovarian cancer, distant tumor implants may be particularly important.

Supported by NIH R01 CA163462 and DOD OC093429.

Citation Format: Lixin Zhang, Raluca Budiu, Joan Brozick, Anda M. Vlad. Novel ovarian cancer transplantable models generated from MUC1KrasPten tumors show in vitro and in vivo heterogeneity. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4976. doi:10.1158/1538-7445.AM2014-4976