Functional analysis of pathways mediating intestinal stem cell plasticity

在肠癌中，表达Lgr5的肠道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，才能使肿瘤发展，从而强调了肿瘤分级组织的概念。我们最近获得的证据表明，在这种层级组织中可以发生细胞可塑性。增强的Wnt信号允许有丝分裂后的上皮细胞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记物，它们就能够启动肿瘤形成。肿瘤干细胞(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射治疗具有抵抗力。因此，旨在消除CSLC的概念对结直肠癌的治疗大有可为。然而，我们发现，消除Lgr5+细胞并不会导致肿瘤的消退，我们已经确定了一条在Lgr5+细胞耗尽时负责维持肿瘤的代偿途径。此外，我们还发现，Lgr5+细胞在被其他肿瘤细胞清除后可以被补充。本项目的目的是确定Lgr5-细胞在已建立的肿瘤中去分化的细胞和分子机制。

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.