Regulation of primary metastasis in high grade serous ovarian cancer

项目摘要/摘要 高级别浆液性卵巢癌(HGSOC)是最常见和最致命的卵巢癌 组织类型。尽管长期以来人们一直认为HGSOC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，还可以从 输卵管从这些前驱病变扩散，并遵循各种局部迁移线索，以便 定植卵巢并建立原发HGSOC肿瘤。卵巢似乎促进了扩张和 卵巢扩散到腹膜腔的其余部分。尽管这种现象有很好的记录，但 促使发育不良的输卵管细胞最初扩散到卵巢的分子机制是 人们对此知之甚少。为了解决这个问题，我们团队开发了一种新的成像质谱学技术 使人们能够前所未有地洞察旁分泌因素，这些因素创造了一个有利于转移的利基市场，并允许 用于输卵管细胞向卵巢的迁移。使用这项技术，我们确定了共培养 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。这一点意义重大，因为去甲肾上腺素是一种既定的 晚期疾病中的肿瘤促进剂，以及服用干扰β受体阻滞剂的卵巢癌患者 去甲肾上腺素信号通常会改善临床结果。然而，去甲肾上腺素在肿瘤中的作用 发展在很大程度上是未知的。鉴于β的广泛可用性、低成本和最小的不良影响- 阻滞剂，去甲肾上腺素是否应同样促进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。考虑到可能会直接影响临床 实践中，有必要进一步剖析指导去甲肾上腺素生物合成的两个机制。 作为去甲肾上腺素在HGSOC发展过程中的下游作用。通过详细的实验， 在这项提议中，我们将获得对这些事件的宝贵见解，希望能够预防或推迟 高危患者HGSOC的发生。

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.