Druggable cancer cell-intrinsic regulators of extracellular communication

可药物化的癌细胞细胞外通讯的内在调节因子

• 批准号: 499289944
• 负责人: Professor Dr. Matthias Lauth
• 金额: --
• 依托单位: Institut für Molekularbiologie und Tumorforschung (IMT)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/499289944?language=en
• 关键词: Druggable; cancer; cell; intrinsic; regulators

Even today, pancreatic ductal adenocarcinoma (PDAC) represents one of the most lethal malignancies with a 5-year survival rate of under 10%. Estimations predict pancreatic cancer to become the 2nd leading cause of death by cancer in the US by 2030. One of the characteristics of the disease is a prominent histological desmoplasia accompanying a pronounced local immune suppression. Tumor cells communicate with immune cells through multiple ways and promote the formation of this immune privilege. Our functional as well as mechanistic understanding of these processes are however insufficient in order to design novel therapeutic approaches. In own previous work, we could show that the tumor cell specific ablation of the PDAC-overexpressed DYRK1B kinase results in defects in extracellular communication. As a result, cancer cells release strongly reduced numbers of extracellular vesicles (EVs) and alter the differentiation of macrophages, eventually culminating in the significant remodeling of the tumor stroma and the blockade of in vivo PDAC growth. In this project, we aim to delineate the molecular mechanisms linking DYRK1B with EVs and the tumor secretome in order to enable us to harness these processes in future therapeutic approaches.

即使在今天，胰腺导管腺癌（PDAC）也是最致命的恶性肿瘤之一，5年生存率低于10%。据估计，到2030年，胰腺癌将成为美国癌症死亡的第二大原因。该疾病的特征之一是显著的组织学结缔组织增生，伴有明显的局部免疫抑制。肿瘤细胞通过多种途径与免疫细胞进行沟通，并促进这种免疫特权的形成。然而，我们对这些过程的功能和机制的理解还不足以设计新的治疗方法。在我们之前的工作中，我们可以证明PDAC过表达的DYRK1B激酶的肿瘤细胞特异性消融导致细胞外通讯缺陷。因此，癌细胞释放的细胞外囊泡（EV）数量大幅减少，并改变巨噬细胞的分化，最终导致肿瘤基质的显著重塑和体内PDAC生长的阻断。在这个项目中，我们的目标是描绘DYRK1B与EV和肿瘤分泌组之间的分子机制，以便使我们能够在未来的治疗方法中利用这些过程。