PI3K-mTOR signaling in stem cells, tissue homeostasis, and cancer

描述(申请人提供)：纯化和研究正常和肿瘤干细胞的技术正在迅速改进，但我们对平衡干细胞增殖和自我更新的信号通路仍然知之甚少。PTEN/PI3K通路是干细胞维持的关键调节因子之一。PTEN是癌症中第二常见的突变肿瘤抑制基因，在一些小鼠干细胞模型中，缺失PTEN是一种肿瘤启动事件。因此，了解PTEN/PI3K依赖的通路如何调控不同的体细胞干细胞命运的分子基础具有广泛的意义。在这项建议中，我们利用小鼠遗传学来开发间充质干细胞中依赖PTEN/PI3K的信号通路的新模型。利用这些模型，我们将全面定义该途径控制间充质干细胞命运、组织动态平衡和肿瘤发展的机制。我们的结果将为正常和肿瘤干细胞调控的分子基础提供关键的见解。 与公共卫生相关：一些肿瘤的生长可能是由表现出干细胞特征的亚群细胞驱动的，例如能够增殖和自我更新。对于其他癌症，一种罕见干细胞的突变可能是肿瘤的始发事件。因此，了解正常干细胞和肿瘤干细胞的分子调控对于正在进行的抗癌斗争具有广泛的临床意义。在这项提案中，我们调查了正常干细胞被调控的分子机制，并询问这些机制的放松如何导致组织生长障碍和癌症。通过更好地了解正常干细胞和肿瘤干细胞的生物学，我们可以更合理地设计癌症治疗方法。

DESCRIPTION (provided by applicant): Techniques to purify and study normal and tumor stem cells are rapidly improving, yet we still understand relatively little about the signaling pathways that balance stem cell proliferation and self-renewal. One pathway emerging as critical regulator of stem cell maintenance is the PTEN/PI3K pathway. PTEN is the second most frequently mutated tumor suppressor in cancer, and in some murine stem cell models, deleting PTEN is a tumor-initiating event. Thus, understanding the molecular basis of how PTEN/PI3K-dependent pathways regulate the fate of diverse somatic stem cells has broad implications. In this proposal, we use mouse genetics to develop novel models of PTEN/PI3K-dependent signaling pathways in mesenchymal stem cells. Using these models, we will comprehensively define the mechanism by which this pathway controls mesenchymal stem cell fate, tissue homeostasis, and tumor development. Our results will provide key insight into the molecular basis of both normal and tumor stem cell regulation. PUBLIC HEALTH RELEVANCE: The growth of some tumors may be driven by a sub-population of cells that exhibit stem cell characteristics, such as being able to proliferate and self-renew. For other cancers, mutation in a rare stem cell could be the tumor-initiating event. Thus, understanding the molecular regulation of both normal and tumor stem cells has broad clinical implications in the ongoing fight against cancer. In this proposal, we investigate the molecular mechanisms by which normal stem cells are regulated, and ask how deregulation of these mechanisms causes tissue growth disorders and cancer. By better understanding the biology of normal and tumor stem cells, we can more rationally design cancer therapies.