Regulation of primary metastasis in high grade serous ovarian cancer

项目总结/摘要 高级别浆液性卵巢癌（HGSOC）是最常见和最致命的卵巢癌 组织型尽管HGSOC长期以来一直被认为起源于卵巢，但最近的证据表明， HGSOC前驱病变实际上起源于输卵管。此外，从细胞中选择发育异常细胞。 输卵管从这些前驱病变扩散，并遵循各种局部迁移线索， 定植于卵巢并形成原发性HGSOC肿瘤。卵巢似乎促进了扩张， 卵巢扩散到腹膜间隙的其余部分。虽然这种现象是有据可查的， 促使发育不良的输卵管细胞最初播散到卵巢的分子机制是 不太了解。为了解决这个问题，我们的团队开发了一种新的成像质谱技术， 允许前所未有的洞察旁分泌因素，创造一个促转移的利基，并允许 用于输卵管细胞向卵巢迁移。使用这种技术，我们确定， 具有发育不良输卵管细胞的小鼠卵巢外植体导致去甲肾上腺素分泌持续增加， 卵巢，后来发现是由卵巢本身产生的。这是重要的，因为去甲肾上腺素是一种公认的 晚期疾病中的肿瘤促进剂，以及服用干扰肿瘤促进剂的β受体阻滞剂的卵巢癌患者 去甲肾上腺素信号通常具有改善的临床结果。然而，去甲肾上腺素在肿瘤中的作用 发展基本上是未知的。鉴于β-羟考酮的广泛可用性、低成本和最小的不良反应， 阻断剂，去甲肾上腺素应该同样促进HGSOC的发展，这可能提供机会 用于高危患者的早期干预和/或化学预防。考虑到可能直接影响临床 实践中，有必要进一步剖析直接去甲肾上腺素生物合成的机制，以及 作为HGSOC发展过程中去甲肾上腺素的下游效应。通过详细的实验 在这一建议中，我们将获得对这些事件的有价值的洞察力，希望能够阻止或推迟这些事件的发生 高危患者中HGSOC的发展。

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.