Role of ANGPTL4 in ovarian carcinoma

ANGPTL4在卵巢癌中的作用

• 批准号: 427340281
• 负责人: Professor Dr. Rolf Müller
• 金额: --
• 依托单位: Zentrum für Tumor- und Immunbiologie (ZTI)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/427340281?language=en
• 关键词: Role; ANGPTL4; ovarian; carcinoma

Ovarian carcinoma (OC) is the most frequent cause of death from a gynecological malignancy. Among the unique features of this disease is its tumor microenvironment, which is comprised by the tumor stroma and the peritoneal fluid (occurring as ascites at advanced stages). The peritoneal fluid is rich in soluble factors, cancer cell spheroids and different types of reeducated host cells that cooperate to establish an environment promoting peritoneal dissemination and immune suppression. Our previous work has established a comprehensive signaling network operating between tumor and host cells in OC ascites and has identified ANGPTL4 as a component within this network. ANGPTL4 is strongly induced by ascites, promotes OC cell invasion and is associated with a poor survival. Nevertheless, the precise role of ANGPTL4 in the metastatic spread of OC cells to peritoneal organs remains unclear. Thus, the potential function of ANGPTL4 in the attachment of OC cancer cells to the mesothelial lining of these organs, in their invasion of the mesothelium and submesothelial layers, in the induction of epithelial-to-mesenchymal transition (EMT) and in the secretion of metastasis-relevant cytokines remain obscure. In the proposed project we intend to shed light on these open questions.ANGPTL4 exerts its pro-invasive properties through binding to membrane receptors (integrins). However, the molecular signaling mechanisms utilized by ANGPTL4 to promote the pro-metastatic properties of OC cells are largely unknown. We therefore intend to link the pro-metastatic functions of ANGPTL4 alluded to above with specific signal transduction pathways. Towards this goal, we will apply (i) a hypothesis-driven approach to analyze the activation state of proteins previously proposed as ANGPTL4-triggered signal transducers, and (ii) an unbiased strategy based on transcriptomics and phosphoproteomics. The central goal of this project is to test the hypothesis that ANGPTL4-induced signaling plays an essential role in OC invasion and metastasis and therefore represents a potential pharmacological target for therapeutic intervention. We will address this question by interfering with its expression or function and determining the impact of this blockade on the ascites-induced pro-metastatic biological functions of OC cells. All studies for this project will be carried out with patient-derived tumor cells and will be complemented by studies in mouse models of peritoneal dissemination.

卵巢癌（OC）是妇科恶性肿瘤最常见的死亡原因。这种疾病的独特特征之一是其肿瘤微环境，由肿瘤基质和腹膜液（晚期以腹水形式出现）组成。腹膜液富含可溶性因子、癌细胞球体和不同类型的再教育宿主细胞，它们合作建立促进腹膜传播和免疫抑制的环境。我们之前的工作已经在 OC 腹水中的肿瘤和宿主细胞之间建立了一个全面的信号网络，并确定 ANGPTL4 是该网络中的一个组成部分。 ANGPTL4 由腹水强烈诱导，促进 OC 细胞侵袭并与较差的存活率相关。然而，ANGPTL4 在 OC 细胞转移至腹膜器官中的确切作用仍不清楚。因此，ANGPTL4 在 OC 癌细胞附着到这些器官的间皮内层、侵袭间皮和间皮下层、诱导上皮间质转化 (EMT) 以及分泌转移相关的细胞因子仍然不清楚。 在拟议的项目中，我们打算阐明这些悬而未决的问题。ANGPTL4 通过与膜受体（整合素）结合发挥其促侵袭特性。然而，ANGPTL4 用于促进 OC 细胞促转移特性的分子信号传导机制在很大程度上尚不清楚。因此，我们打算将上面提到的 ANGPTL4 的促转移功能与特定的信号转导途径联系起来。为了实现这一目标，我们将应用（i）假设驱动的方法来分析先前提出的 ANGPTL4 触发信号转导器的蛋白质的激活状态，以及（ii）基于转录组学和磷酸化蛋白质组学的无偏见策略。该项目的中心目标是检验以下假设：ANGPTL4 诱导的信号传导在 OC 侵袭和转移中发挥重要作用，因此代表了治疗干预的潜在药理学靶点。我们将通过干扰其表达或功能并确定这种阻断对腹水诱导的 OC 细胞促转移生物学功能的影响来解决这个问题。该项目的所有研究都将使用患者来源的肿瘤细胞进行，并将通过腹膜传播小鼠模型的研究进行补充。