Regulation of primary metastasis in high grade serous ovarian cancer

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Project Summary/Abstract High grade serous ovarian cancer (HGSOC) is both the most common and most lethal ovarian cancer histotype. Though HGSOC has been long thought to originate in the ovary, recent evidence now suggests that HGSOC precursor lesions in fact originate in the fallopian tube. Further, select dysplastic cells from the fallopian tube disseminate from these precursor lesions and follow a variety of local migratory cues in order to colonize the ovary and establish a primary HGSOC tumor. The ovary seems to facilitate the expansion and spread of the ovary to the rest of the peritoneal space. Though this phenomenon is well documented, the molecular mechanisms that drive the initial dissemination of dysplastic fallopian tube cells to the ovary are poorly understood. To address this, our group has developed a new imaging mass spectrometry technique that has allowed for unprecedented insight into the paracrine factors that create a pro-metastatic niche and allow for the migration of fallopian tube cells toward the ovary. Using this technique, we determined that co-culture of murine ovary explants with dysplastic tubal cells leads to consistent increases in norepinephrine secretion from the ovary, later found to be produced by the ovary itself. This is significant, as norepinephrine is an established tumor promoter in advanced disease, and ovarian cancer patients taking β-blockers that interfere with norepinephrine signals typically have improved clinical outcomes. However, the role of norepinephrine in tumor development is largely unknown. Given the wide availability, low cost, and minimal adverse effects of β- blockers, should norepinephrine similarly enhance the development of HGSOC this may provide opportunity for early intervention and/or chemoprevention in high-risk patients. Given the potential to directly impact clinical practice, it is essential to further dissect both the mechanisms that direct norepinephrine biosynthesis, as well as the downstream effects of norepinephrine during HGSOC development. Through the experiments detailed in this proposal, we will gain valuable insight into these events in hopes of either preventing or delaying HGSOC development in high-risk patients.