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Regulation of primary metastasis in high grade serous ovarian cancer

高级别浆液性卵巢癌原发转移的调节

基本信息

批准号：
10608098
负责人：
Tova Bergsten
金额：
$ 5.27万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-16 至 2025-05-15
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10608098
关键词：
Address Adrenergic Agents Adrenergic beta-Antagonists Adverse effects Anabolism Automobile Driving CRISPR/Cas technology Cancer Biology Cancer Patient Cells Chemicals Chemoprevention Clinical Clinical Management Coculture Techniques Communication Cues Data Development Diagnosis Disease Disease Progression Distant Metastasis Early Intervention Epithelial Cells Epithelium Event FDA approved Goals Human Immunotherapy Invaded Lesion Malignant - descriptor Malignant Neoplasms Malignant neoplasm of ovary Mammalian Oviducts Mediator Molecular Mus Mutation Neoplasm Metastasis Norepinephrine Osteonectin Outcome Ovarian Ovary PI3K/AKT Pathway interactions Patient Care Patients Peritoneal Pharmaceutical Preparations Physicians Production Prognosis Propranolol Radiation therapy Refractory Regulation Rest Role Scientist Series Serous Signal Transduction Soil Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization System TP53 gene Techniques Testing Time Training Translating Tumor Promoters Tumor Suppressor Proteins Up-Regulation Woman Xenograft procedure advanced disease antagonist beta-2 Adrenergic Receptors beta-adrenergic receptor clinical practice cost drug repurposing expectation experimental study high risk improved improved outcome inhibitor insight malignant phenotype mass spectrometric imaging migration neoplastic cell novel strategies ovarian neoplasm overexpression paracrine pharmacologic precision medicine prevent receptor release factor response small hairpin RNA standard of care tumor tumor progression tumorigenic

项目摘要

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.

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。虽然HGSOC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。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Fallopian tube secreted protein affects ovarian metabolites in high grade serous ovarian cancer.

DOI：
10.3389/fcell.2022.1042734
发表时间：
2022
期刊：
Frontiers in cell and developmental biology
影响因子：
5.5
作者：
通讯作者：

Home-Built Spinning Apparatus for Drying Agarose-Based Imaging Mass Spectrometry Samples.

DOI：
10.1021/jasms.2c00044
发表时间：
2022-07-06
期刊：
JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMETRY
影响因子：
3.2
作者：
Lusk, Hannah J.;Levy, Sarah E.;Bergsten, Tova M.;Burdette, Joanna E.;Sanchez, Laura M.
通讯作者：
Sanchez, Laura M.

Kaempferol, a Phytoprogestin, Induces a Subset of Progesterone-Regulated Genes in the Uterus.