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 Lgr5 的肠干细胞构成了起源细胞。 Wnt 通路中的激活突变必须发生在这些细胞中才能形成肿瘤，从而强调了肿瘤分层组织的概念。我们最近获得的证据表明，细胞可塑性可以发生在这种等级组织中。增强的 Wnt 信号传导允许有丝分裂后上皮细胞去分化并重新获得干细胞基因。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）被认为对于肿瘤维持至关重要。此外，CSLC 已被证明对化疗和放疗具有抵抗力。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，我们发现消除 Lgr5+ 细胞不会导致肿瘤消退，并且我们已经确定了一种补偿途径，负责 Lgr5+ 细胞消除后肿瘤的维持。此外，我们发现Lgr5+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已形成肿瘤中 Lgr5- 细胞去分化所涉及的细胞和分子机制。