Epithelial-mesenchymal transition in stem cell induction and maintenance

描述（由申请人提供）：了解参与诱导和维持癌症干细胞（CSC）的机制对于开发可以有效靶向CSC的疗法至关重要。越来越多的证据表明，这些机制通常由CSC和正常干细胞共享。因此，对正常干细胞的研究产生了对癌症干细胞生物学的重要见解。上皮-间充质转化已显示赋予分化的乳腺上皮细胞干细胞样性质（Mani等人，Cell 2008）。然而，目前尚不清楚EMT是否在真正的乳腺干细胞诱导和维持中发挥作用。目前还没有严格证明EMT可以诱导乳腺癌干细胞。此外，EMT激活干细胞程序的机制尚不清楚。为了检查EMT在干细胞诱导中的作用，将诱导原代乳腺上皮细胞（MEC）和癌细胞经历瞬时EMT，然后测试干细胞活性的增加。还将测试EMT将分化细胞转化为干细胞的能力。包括基因敲除和敲低在内的功能丧失方法将用于测试在维持乳腺干细胞和乳腺癌干细胞中对EMT诱导因子的需求。参与干细胞相关的信号通路介导激活的干细胞程序的EMT也将在本提案中进行审查。 这些研究的积极成果将有助于更好地理解正常干细胞和癌症干细胞的生物学特性，并有助于开发癌症干细胞靶向疗法。此外，了解EMT和真正的干细胞的联系将有助于产生正常的上皮干细胞用于研究和治疗用途。

DESCRIPTION (provided by applicant): Understanding the mechanisms involved in the induction and maintenance of cancer stem cells (CSCs) is critical for developing therapies that can target CSCs effectively. Increasing evidence has suggested such mechanisms are often shared by both CSCs and normal stem cells. Therefore, studies in normal stem cells yield important insights into the cancer stem cell biology. The epithelial-mesenchymal transition has been shown to confer differentiated mammary epithelial cells stem cell-like properties (Mani et al. Cell 2008). However, it is not clear whether the EMT plays a role in bona fide mammary stem cell induction and maintenance. It is also not yet rigorously demonstrated that the EMT can induce breast cancer stem cells. In addition, the mechanism by which the EMT activates stem-cell program is unknown. To examine the role of the EMT in the induction of stem cells, primary mammary epithelial cells (MECs) and cancer cells will be induced to undergo transient EMTs, and then tested for increases in stem cell activities. The ability of EMTs in converting differentiated cells into stem cells will also be tested. Loss-of-function approaches, including gene knock-out and knock-down, will be used to test the requirement of EMT- inducing factors in the maintenance of mammary stem cells and breast cancer stem cells. The involvement of stem cell-related signaling pathways in mediating the activation of the stem-cell program by the EMT will be also examined in this proposal. Positive outcomes ofthese studies will lead to better understanding ofthe biology of normal stem cells and cancer stem cells and help developing cancer stem cell-targeted therapies. In addition, understanding the link of EMT and bona fide stem cells will help generating normal epithelial stem cells for research and therapeutic uses.