The role of syntenin in the establishment of a favorable tumor microenvironment in human breast cancer

乳腺癌是全世界妇女中最常见的癌症，占世界卫生组织（世卫组织）欧洲区域癌症病例总数的28%。乳腺癌是一种复杂的组织，肿瘤细胞被多种良性基质细胞（如结缔组织细胞、免疫细胞或血管细胞）所包围。肿瘤细胞能够影响这些基质细胞，从而创造有利的肿瘤生态位，促进肿瘤进展。最近的研究表明，这些肿瘤-基质相互作用主要是由细胞外囊泡介导的。这些小囊泡（直径<1µm）从细胞内部或细胞表面释放出来，能够将分子运输到周围的细胞。然而，调控囊泡介导的肿瘤-间质通讯的特定因子和可能代表有希望的新治疗靶点仍然未知。对患者样本的分析显示，在晚期人类乳腺癌中，syntenin蛋白过度表达，其表达水平与患者生存率呈负相关。有趣的是，syntenin控制细胞外囊泡的生物发生和各种肿瘤支持蛋白向这些囊泡的出口。然而，syntenin阳性囊泡在肿瘤-间质相互作用中的意义迄今尚未得到研究。目前的项目将通过首先使用蛋白质组学方法来确定哪些肿瘤支持蛋白通过syntenin输出到肿瘤囊泡来解决这个问题。随后，将在体外和同基因乳腺癌小鼠模型中评估syntenin阳性囊泡对肿瘤-间质相互作用的意义。新型的syntenin抑制剂将测试其对抗肿瘤前肿瘤-间质串扰的效率。

Breast cancer is the most common cancer in women worldwide and accounts for 28% of the total cancer cases in the European Region of the World Health Organisation (WHO). Breast cancers compose complex tissues whereby tumor cells are surrounded by a variety of benign stroma cells (e.g. cells of the connective tissue, immune cells or blood vessel cells). The tumor cells are able to influence these stroma cells, thereby creating a favorable tumor niche which promotes tumor progression. Recent studies show that these tumor-stroma interactions are largely mediated by extracellular vesicles. These are small vesicles (diameter <1µm) which are released from inside the cell or from the cell surface and are able to transport molecules to surrounding cells. However, specific factors which regulate vesicle-mediated tumor-stroma communication and might represent promising novel targets for therapy are still unknown. Analyses of patient samples revealed that the protein syntenin is overexpressed in advanced human breast cancer, its expression level inversely correlating with patient survival. Interestingly, syntenin controls the biogenesis of extracellular vesicles and the export of various tumor-supporting proteins to these vesicles. However, the significance of syntenin-positive vesicles for tumor-stroma interactions has not been investigated so far. The present project will address this question by first using a proteomics approach to identify which tumor-supporting proteins are exported to tumor vesicles by syntenin. Subsequently, the significance of syntenin-positive vesicles for tumor-stroma interactions will be assessed in vitro and in a syngeneic mouse model of breast cancer. Novel syntenin inhibitors will be tested for their efficiency to antagonize the pro-tumoral tumor-stroma crosstalk.