Accumulating evidence suggests that the most common subtype of ovarian carcinoma (OC), high-grade serous carcinoma (HGSC), frequently originates from the fallopian tube. This discovery has shifted the way the field thinks about tumor development and underscored the need to understand the mechanisms underlying spread or metastasis to ovary. Our lab developed and characterized a transgenic mouse model, Tg-MISIIR-TAg-DR26, that develops spontaneous bilateral OC with evidence of oviductal (equivalent to fallopian tube in mouse) tumor origins. We observe dysplastic lesions within the oviduct as well as expression of several epithelial oviductal proteins (FOXJ1 and PAX8) in ovary tumors. Akin to human ovarian cancer progression, these mice develop frequent ascites and peritoneal metastasis. An additional line derived from the same transgene construct, Tg- MISIIR-TAg-DG61, develops primary oviductal carcinomas that infrequently spread to ovary or result in the production of ascites. Although we observe different pathological outcomes when comparing Tg-MISIIR-TAg- DR26 and ?DG61 animals, our preliminary evidence indicated that both begin as dysplastic oviductal lesions, therefore we hypothesize that inherent, identifiable molecular factors drive the ability of tumors in DR26 mice to rapidly migrate to and invade the ovary, and that expression of these factors are either absent or altered in oviductal tumors arising in DG61 mice. We will utilize these physiologically relevant models to better understand the development of human disease by elucidating molecular factors required for spread of oviductal lesions to the ovary and beyond. This will be achieved by using a candidate gene approach and unbiased RNA-sequencing analysis and comparison between Tg-MISIIR-TAg lines following by in vitro and in vivo validation of candidate genes responsible for tumor homing to ovary. Ultimately this work will aid in understanding of disease development and progression which is essential to the identification of therapeutic targets and improved diagnosis and treatment.
The proposed study will provide detailed genetic data from controlled and pathologically relevant in vivo models of OC. This work will advance our understanding of what genetic/molecular factors restrain the spread of fallopian lesions as well as those signals that result in their movement to and seeding of the ovary. Additionally, we predict these analyses will elucidate novel factors that support tumor growth and dissemination that may have clinical value as prognostic biomarkers and therapeutic targets.