Functional analysis of pathways mediating intestinal stem cell plasticity

介导肠道干细胞可塑性途径的功能分析

• 批准号: 319465372
• 负责人: Professor Dr. Florian R. Greten
• 金额: --
• 依托单位: Georg-Speyer-Haus, Institut für Tumorbiologie und experimentelle Therapie
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/319465372?language=en
• 关键词: Functional; analysis; pathways; mediating; intestinal

In intestinal cancer, Lgr5 expressing intestinal stem cells comprise the cells of origin. Activating mutations in the Wnt pathway have to occur in these cells for a tumor to develop thus underscoring the concept of hierarchical organization of a tumor. We recently obtained evidence that cell plasticity can occur in this hierarchical organization. Enhanced Wnt signaling allows dedifferentiation of post-mitotic epithelial cells and reacquisition of stem cell genes. Once these cells re-express stem cell markers, they are capable of initiating tumorigenesis. Cancer stem like cells (CSLC) are considered essential for tumor maintenance. Moreover, CSLC have been shown to be resistant to chemo- and radiotherapy. Therefore, concepts aiming to eliminate CSLC hold great promise for the therapy of CRC. However, we found that elimination of Lgr5+ cells does not lead to tumor regression and we have identified a compensatory pathway that is responsible for tumor maintenance upon Lgr5+ cell depletion. Moreover, we found that Lgr5+ cells can be replenished after their elimination by other tumor cells. The aim of this project is to identify the cellular and molecular mechanism involved in dedifferentiation of Lgr5- cells in established tumors.

在肠癌中，表达Lgr 5的肠干细胞包括起源细胞。Wnt通路中的激活突变必须发生在这些细胞中以使肿瘤发展，因此强调了肿瘤的分级组织的概念。我们最近获得的证据表明，细胞可塑性可以发生在这个层次组织。增强的Wnt信号传导允许有丝分裂后上皮细胞的去分化和干细胞基因的重新获得。一旦这些细胞重新表达干细胞标志物，它们就能够启动肿瘤发生。癌症干细胞样细胞（CSLC）被认为是肿瘤维持所必需的。此外，CSLC已被证明对化疗和放疗具有抗性。因此，旨在消除CSLC的概念为CRC的治疗带来了巨大的希望。然而，我们发现Lgr 5+细胞的消除不会导致肿瘤消退，并且我们已经确定了一种补偿途径，该途径负责Lgr 5+细胞耗尽后的肿瘤维持。此外，我们发现Lgr 5+细胞在被其他肿瘤细胞消除后可以得到补充。该项目的目的是确定在已建立的肿瘤中Lgr 5-细胞的去分化所涉及的细胞和分子机制。