The role of the Wnt5a/Frizzled5 signaling axis in the development and therapy of helicobacter-associated gastric cancer arising from epithelial stem cells

胃癌是世界范围内最常见的胃肠道肿瘤之一，其预后仍然很差。手术切除是唯一有效的治疗方法，但大多数患者接受术前化疗。对这种治疗的反应率在每个患者中不同，直到今天，还没有可靠的参数预测术前治疗的反应。这种不同反应的一个潜在原因是肿瘤干细胞。在过去的几年中，已经描述了胃上皮中的几种潜在的干细胞群。在这个项目中，我们的目的是研究FZD 5/Wnt 5a信号轴在胃癌发生发展中的相关性。在第一步中，我们将对人体组织进行FZD 5染色，并对Wnt 5a进行原位杂交，因为Wnt 5a的免疫组织化学检测非常具有挑战性。先前的研究已经表明先天淋巴样细胞2型（ILC-2）是胃中Wnt 5a的主要来源，因此我们也将对这些细胞进行染色。这些参数将与临床患者数据相关联，以评估这些标志物在人胃癌中表达的潜在预后价值。在下一步中，我们将详细研究不同小鼠模型中的信号传导轴。对于这些实验，可以使用不同的小鼠模型，其中可以敲除这些基因。这些动物将感染螺杆菌ssp。引发炎症幽门螺杆菌的慢性感染是人类发生胃癌的主要危险因素之一。使用FACS分离，我们将分析FZD 5+干细胞并使用类器官研究干细胞性。此外，我们的目标是使用RNA测序来确定潜在的治疗靶点。将使用人体样本验证和检测这些实验的结果的预后相关性。本研究将有助于提高对幽门螺杆菌慢性感染后胃癌发生发展的认识，并将为改善胃癌患者的治疗提供重要的知识。

Gastric cancer is one of the most frequent types of gastrointestinal cancer worldwide and the outcome is still poor. The surgical resection is the only curative treatment but the majority of the patients receives preoperative chemotherapy. The response rates to this therapy vary in each patient and until today, there is no reliable parameter predicting the response to preoperative therapy. One potential reason for this different response are tumor stem cells. In the last years several potential stem cell population in the gastric epithelium have been described. In this project we aim to investigate the relevance of the FZD5/Wnt5a signaling axis on the development of gastric cancer. In a first step we will stain human tissue for FZD5 and perform in-situ hybridisation for Wnt5a since immunhistochemical detection of Wnt5a is quite challenging. Previous studies have shown innate lymphoid cells type 2 (ILC-2) as a major source of Wnt5a in the stomach so that we will perform staining for these cells as well. These parameters will correlated with the clinical patient data to evaluate the potential progonostic value of the expression of these markers in human gastric cancer. In a next step we will investigate this signaling axis in different murine models in detail. For these experiments, different mouse models are available in which these genes can be knocked out. These animals will be infected with Helicobacter ssp. that induce an inflammation. Chronic infection with Helicobacter represents one of the major risks factors for the development of gastric cancer in humans. Using FACS-isolation we will analyse FZD5+ stem cells and investigate the stemness using organoids. Additionally, we aim to identify potential therapeutic targets using RNA-sequencing. The results from these experiment will be validated and tested for the prognostic relevance using the human samples. This project will help to improve the understanding of gastric cancer development following chronic infection with Helicobacter and will provide important knowledge for the improvement of therapy in gastric cancer patients.