The Hippo Signaling Pathway in High Grade Serous Ovarian Carcinoma

项目概述：卵巢高级别浆液性癌（HGSC）是最致命的妇科癌症。 卵巢HGSC的病因在很大程度上是未知的。尽管最近的研究（包括我们的研究）已经确定了 输卵管上皮细胞（FTECs）作为卵巢HGSC的起源细胞，其确切的分子机制 HGSC从FTEC的潜在起始仍不清楚。在第一个资助期内，我们的研究成果提供了 有力的证据表明，Hippo/雅普信号通路的破坏在恶性肿瘤中起着关键作用。 永生化FTECs的转化和HGSC从永生化输卵管的发育， 卵巢上皮细胞尽管有这些发现，我们发现从小鼠诱导HGSC是具有挑战性的， 超活化YAP 1的细胞特异性表达对输卵管上皮的影响。我们的机械研究，出乎意料的， 结果表明，在培养的原代FTEC中，YAP 1单独过度活化诱导细胞衰老。 这一令人惊讶的发现表明，其他因素可能会阻止FTECs从YAP 1诱导的衰老过程中， 恶性转化过程。在恶性肿瘤诱导中辅助过度活化的YAP 1的因子 FTEC的转化是未知的。我们的大规模筛查研究表明， 乳头瘤病毒（HPV）足以防止培养的原代FTECs从过度活化的YAP 1诱导的 衰老与此同时，我们前期的研究表明，HPV 16 E6癌蛋白抑制Hippo 途径和稳定的YAP 1蛋白，以促进YAP 1的致癌作用。有趣的是，我们初步的 研究表明，YAP 1通过增加以下蛋白的表达，促进培养的FTEC的HPV感染： HPV受体分子和抑制先天性免疫。重要的是，HPV病毒体可以在 生理（精子传递）和病理（通过月经逆行）条件。基于 根据以上证据，我们推测，通过上调假定的HPV受体， 分子和抑制先天免疫，利用HPV克服癌基因诱导的衰老， 形成YAP 1-HPV致癌联盟以驱动输卵管上皮中HGSC的起始。在这个项目中， 我们设计了三个具体目标来验证我们的假设。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， 分离的小鼠乳头瘤病毒（MmuPV 1）。在具体目标2中，我们设计了实验来揭示分子 YAP 1-HPV联盟驱动输卵管癌变的机制。在具体目标3中，我们 设计了临床前研究，以评估联合靶向HPV和YAP 1的潜在临床应用 在预防和早期检测FTEC衍生的HGSC中的作用。完成拟议的研究可以 确定HPV是卵巢癌一个被忽视的可预防的危险因素。确定职能 YAP 1-HPV致癌轴在输卵管上皮癌变中的机制将提供 为制定策略以改善FTEC衍生HGSC的预防和早期检测提供了新的线索。

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.