Lysophosphatidic acid-mediated resistance in ovarian carcinoma

溶血磷脂酸介导的卵巢癌耐药

• 批准号: 284839430
• 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: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/284839430?language=en
• 关键词: Lysophosphatidic; acid; mediated; resistance; ovarian

Serous ovarian carcinoma has a dire prognosis and ranks fifth as the cause of death from cancer in women, mainly due to the regrowth of tumors after clinically successful first-line adjuvant chemotherapy and the selection for resistant tumor cells. The underlying mechanisms remain largely elusive, but are likely to involve chemoresistant tumor cells and spheroids floating in the peritoneal effusion (ascites). After adhesion to serous membranes, these cells invade through the mesothelium and upon contact with the extracellular matrix proliferate to form transcoelomic metastases. Multiple lines of evidence suggest that both tumor progression and therapy resistance are promoted by tumor-associated macrophages (TAMs).Human serous ovarian carcinoma represents a unique experimental system, since it not only allows the isolation of large numbers of primary tumor cells and immune cells from ascites, but also provides the opportunity to culture these cells in autologous ascites fluid without any artificial additives. Using this system, we have been able to isolate from the ascites of individual untreated patients chemoresistant as well as chemosensitive tumor cell spheroids. Moreover, chemotherapy of the chemosensitive spheroids results in the selection of chemoresistant cells, thus providing systems for the studying both primary and therapy-induced resistance. Comparative RNA-Seq experiments led to the association of the lysophosphatidic acid (LPA) receptor gene LPAR3 with chemoresistance, and identified LPAR6 as a TAM-specific receptor gene. The enzymatic generation of LPA, a known mediator of poor clinical outcome, is critically dependent on secreted phospholipases A2 and autotaxin. Our RNA-Seq analyses showed that TAMs express several genes coding for these enzyme (PLA2G7, ENPP2) at much higher levels than tumor cells, pointing to a cooperation between both cell types in LPA-mediated signaling. Based on these observations we propose to address the following specific goals:(i) We will systematically study LPA signaling components in tumor cells, TAMs and ascites fluid and will investigate potential associations with tumor relapse (Reinartz).(ii) We will define LPAR-triggered signaling pathways in these cells by establishing transcriptional signaling networks and analyzing the function of specific signaling components (Müller).(iii) We will address the role of LPA signaling pathways in chemoresistance and matrix interaction (Müller).(iv) We will analyze the role of LPA in the polarization of TAMs and the putative cooperation of tumor cells and TAMs in LPA generation and signaling in co-culture systems (Reinartz).Ultimately, the goal of this project is to provide the basis for an optimal clinical development of drugs directed at the LPA signaling network and an improvement of the adjuvant therapy of ovarian cancer.

浆液性卵巢癌的预后很差，在女性癌症死亡原因中排名第五，这主要是由于临床成功的一线辅助化疗后肿瘤的再生长以及耐药肿瘤细胞的选择，其潜在机制在很大程度上仍不清楚。但可能涉及漂浮在腹腔积液（腹水）中的化疗耐药肿瘤细胞和球体，这些细胞在粘附到浆膜后，通过间皮侵入并与腹水接触。细胞外基质增殖形成跨体腔转移细胞系 多个证据表明肿瘤相关巨噬细胞 (TAM) 促进肿瘤进展和治疗耐药。人类浆液性卵巢癌代表了一个独特的实验系统，因为它不仅允许分离大量细胞。腹水中的原代肿瘤细胞和免疫细胞，而且还提供了在自体腹水中培养这些细胞的机会，无需任何人工添加剂，使用该系统，我们已经能够从腹水中分离出来。此外，对化疗敏感的肿瘤细胞球体进行化疗会导致化疗耐药细胞的选择，从而为研究原发性和治疗诱导的耐药性提供了系统。溶血磷脂酸 (LPA) 受体基因 LPAR3 与化疗耐药性的关联，并将 LPAR6 鉴定为 TAM 特异性受体基因。临床结果不佳，很大程度上取决于分泌的磷脂酶 A2 和自分泌运动因子，我们的 RNA-Seq 分析表明，TAM 表达编码这些酶的多个基因（PLA2G7、ENPP2）的水平比肿瘤细胞高得多，表明两种细胞类型之间存在协同作用。基于这些建议，我们建议实现以下具体目标：(i) 我们将系统地研究肿瘤细胞、TAM 和腹水中的 LPA 信号成分，并研究与肿瘤的潜在关联。 (Reinartz)。(ii) 我们将通过建立转录信号网络并分析特定信号成分的功能来定义这些细胞中 LPAR 触发的信号通路 (Müller)。(iii) 我们将讨论 LPA 信号通路在化疗耐药中的作用(iv) 我们将分析 LPA 在 TAM 极化中的作用以及肿瘤细胞和 TAM 在共培养系统中 LPA 生成和信号传导中的假定合作(Reinartz)。最终，该项目的目标是为针对 LPA 信号网络的药物的最佳临床开发和卵巢癌辅助治疗的改进提供基础。