The Hippo Signaling Pathway in High Grade Serous Ovarian Carcinoma

高级别浆液性卵巢癌中的 Hippo 信号通路

• 批准号: 10211391
• 负责人: Cheng Wang
• 金额: $ 32.33万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10211391
• 关键词: Achievement; Animal Model; Artificial Insemination; Award; Carcinoma; Cell Aging; Cell Cycle Arrest; Cells; Data; Development; Early Diagnosis; Epithelial; Epithelial Cells; Etiology; Fallopian Tube Carcinoma; Fluorescence; Funding; HPV-High Risk; Human; Human Papillomavirus; Human papilloma virus infection; Human papillomavirus 16; Image; Imaging technology; Immunization; In Vitro; Lead; Malignant - descriptor; Malignant Epithelial Cell; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Mammalian Oviducts; Modeling; Molecular; Mus; Natural Immunity; Oncogenes; Oncogenic; Oncoproteins; Ovarian; Ovarian Serous Adenocarcinoma; Ovary; Papillomavirus; Pathologic; Pathway interactions; Pelvic cavity structure; Pharmaceutical Preparations; Physiological; Play; Predisposition; Prevention; Process; Proteins; Protocols documentation; Publications; Publishing; Reporter; Research; Retrograde Menstruation; Risk Factors; Role; Serous; Signal Pathway; Solid; Survival Rate; Testing; Transgenic Animals; Transgenic Mice; Tumor-Derived; Vaccination; Virion; base; cancer imaging; carcinogenesis; carcinogenicity; clinical application; design; experimental study; exposed human population; improved; in vivo Model; mouse model; neglect; neoplastic cell; novel; novel chemoprevention; novel strategies; preclinical study; prevent; receptor; role model; screening; senescence; sperm cell; tool; transmission process; tumorigenesis

PROJECT SUMMARY: Ovarian high-grade serous carcinoma (HGSC) is the most lethal gynecological cancer. The etiology of ovarian HGSC is largely unknown. Although recent studies (including ours) have identified the fallopian tube epithelial cell (FTECs) as a cell-of-origin of ovarian HGSC, the exact molecular mechanism(s) underlying initiation of HGSC from FTECs are still unclear. In the first funded period, our research results provide solid evidence that the disruption of the Hippo/YAP signaling pathway plays a critical role in the malignant transformation of immortalized FTECs and the development of HGSC from the immortalized fallopian tube and ovarian epithelial cells. Despite these findings, we found that it is challenging to induce HGSC from mouse oviduct epithelium by cell-specific expression of hyperactivated YAP1. Our mechanistic studies, unexpectedly, demonstrated that hyperactivation of YAP1 alone in the cultured primary FTEC induced cellular senescence. This surprising finding suggested that other factors likely prevent FTECs from YAP1-induced senescence during the malignant transformation process. The factor(s) that aid hyperactivated YAP1 in the induction of malignant transformation of FTECs are unknown. Our large-scale screening studies showed that infection of human papillomavirus (HPV) was sufficient to prevent cultured primary FTECs from hyperactivated YAP1-induced senescence. Consistently, our previous studies have shown that HPV16 E6 oncoprotein suppressed the Hippo pathway and stabilized YAP1 protein to promote the oncogenic action of YAP1. Intriguingly, our preliminary studies demonstrated that YAP1 facilitated HPV infection of cultured FTECs by increasing the expression of HPV receptor molecules and suppressing the innate immunity. Importantly HPV virions could reach FTECs under both physiological (sperm-transmission) and pathological (via retrograde menstruation) conditions. Based on the above evidence, we hypothesize that hyperactivated YAP1, via upregulating the putative HPV receptor molecules and suppressing the innate immunity, employs HPV to overcome oncogene-induced senescence and forms a YAP1-HPV oncogenic alliance to drive the initiation of HGSC in fallopian tube epithelium. In this project, we designed three specific aims to test our hypothesis. In specific aim 1, we will model the carcinogenic action of the YAP1-HPV alliance in fallopian tube epithelial cells using unique transgenic animal models and newly isolated mouse papillomavirus (MmuPV1). In specific aim 2, we designed experiments to reveal the molecular mechanism(s) by which the YAP1-HPV alliance drives fallopian tube carcinogenesis. In specific aim 3, we designed preclinical studies to evaluate the potential clinical applications of combined targeting HPV and YAP1 in the prevention and early detection of HGSC-derived from FTECs. Achieving the proposed studies could identify HPV as a neglected preventable risk factor for ovarian cancer. Identification of the functioning mechanism (s) of the YAP1-HPV oncogenic axis in the carcinogenesis of fallopian tube epithelium will provide new clues for developing strategies to improve the prevention and early detection of FTEC-derived HGSC.

项目摘要：卵巢高级别浆液性癌 (HGSC) 是最致命的妇科癌症。 卵巢 HGSC 的病因尚不清楚。尽管最近的研究（包括我们的）已经确定 输卵管上皮细胞（FTEC）作为卵巢 HGSC 的起源细胞，其确切的分子机制 FTEC 产生 HGSC 的根本原因仍不清楚。在第一个资助期间，我们的研究成果提供了 确凿的证据表明 Hippo/YAP 信号通路的破坏在恶性细胞癌变中发挥着关键作用 永生化 FTEC 的转化以及永生化输卵管和 HGSC 的发育 卵巢上皮细胞。尽管有这些发现，我们发现从小鼠中诱导 HGSC 具有挑战性 输卵管上皮细胞特异性表达过度激活的 YAP1。我们的机制研究出乎意料地 证明在培养的原代 FTEC 中单独过度激活 YAP1 会诱导细胞衰老。 这一令人惊讶的发现表明，其他因素可能会阻止 FTEC 在 YAP1 诱导的衰老过程中发挥作用。 恶变过程。帮助过度激活 YAP1 诱导恶性细胞的因素 FTEC 的转化尚不清楚。我们的大规模筛查研究表明，人类感染 乳头瘤病毒 (HPV) 足以防止培养的原代 FTEC 受到过度激活的 YAP1 诱导 衰老。一致地，我们之前的研究表明 HPV16 E6 癌蛋白抑制 Hippo 途径和稳定 YAP1 蛋白以促进 YAP1 的致癌作用。有趣的是，我们的初步 研究表明，YAP1 通过增加 FTEC 的表达来促进培养的 FTEC 的 HPV 感染 HPV 受体分子和抑制先天免疫。重要的是，HPV 病毒粒子可以在以下条件下到达 FTEC： 生理（精子传播）和病理（通过逆行月经）条件。基于 根据上述证据，我们假设 YAP1 过度激活，通过上调假定的 HPV 受体 分子并抑制先天免疫，利用 HPV 来克服癌基因诱导的衰老和 形成 YAP1-HPV 致癌联盟，以驱动输卵管上皮中 HGSC 的启动。在这个项目中， 我们设计了三个具体目标来检验我们的假设。在具体目标 1 中，我们将模拟致癌作用 使用独特的转基因动物模型和新方法研究输卵管上皮细胞中的 YAP1-HPV 联盟 分离的小鼠乳头瘤病毒（MmuPV1）。在具体目标 2 中，我们设计了实验来揭示分子 YAP1-HPV 联盟驱动输卵管癌发生的机制。在具体目标 3 中，我们 设计了临床前研究来评估联合靶向 HPV 和 YAP1 的潜在临床应用 预防和早期检测源自 FTEC 的 HGSC。实现拟议的研究可以 将 HPV 确定为卵巢癌的一个被忽视的可预防危险因素。功能识别 YAP1-HPV致癌轴在输卵管上皮癌发生中的机制将提供 制定策略以改善 FTEC 衍生的 HGSC 的预防和早期检测的新线索。