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

乳腺癌是世界范围内女性最常见的癌症，占世界卫生组织（WHO）欧洲区域癌症病例总数的28%。乳腺癌由复杂的组织组成，其中肿瘤细胞被各种良性基质细胞（例如结缔组织细胞、免疫细胞或血管细胞）包围。肿瘤细胞能够影响这些基质细胞，从而产生促进肿瘤进展的有利肿瘤小生境。最近的研究表明，这些肿瘤间质的相互作用主要是由细胞外囊泡介导的。这些是小泡（直径<1µm），从细胞内部或细胞表面释放，能够将分子转运到周围细胞。然而，调节囊泡介导的肿瘤间质通讯的特定因子，以及可能代表有前途的治疗新靶点，仍然是未知的。对患者样本的分析显示，蛋白质syntenin在晚期人类乳腺癌中过表达，其表达水平与患者存活率呈负相关。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输出。然而，syntenin阳性囊泡的肿瘤间质相互作用的意义还没有调查到目前为止。本项目将解决这个问题，首先使用蛋白质组学的方法来确定哪些肿瘤支持蛋白输出到肿瘤囊泡的syntenin。随后，将在体外和乳腺癌的同基因小鼠模型中评估突触蛋白阳性囊泡对于肿瘤-基质相互作用的意义。将测试新型突触蛋白抑制剂拮抗促肿瘤肿瘤-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.