Identification of signals that extrude an apoptotic cell from an epithelium

我发现了一种叫做“挤出”的机制，通过这种机制，垂死的细胞离开上皮细胞 而不破坏该层的阻挡功能。在这里，一个注定死亡的细胞，发出信号， 包围邻近细胞形成细胞间肌动球蛋白环， 垂死的细胞。虽然诱导细胞死亡（凋亡）的刺激激活挤出，我们有 还发现细胞凋亡和挤压并不相互依赖。这表明挤压 在其它情况下可从上皮中除去细胞。促进挤出的信号 因此，当细胞在发育分化过程中离开上皮时， 肿瘤细胞转移的启动。因为大多数高级别肿瘤的基因突变 细胞凋亡途径，阻断细胞凋亡但不挤出的突变可以使肿瘤细胞 容易离开上皮并开始转移到其他部位。因为转移是 通常与癌症的致命性有关，我们相信，了解这些信号， 驱动挤出可能是最重要的。我们还将探讨挤压是否可能先于 并在正常的体内平衡过程中诱导过度拥挤区域的凋亡， 细胞数量。 识别触发挤压的信号将是理解挤压的关键。 挤压所发挥的生理功能。我们计划确定信号通路， 启动承诺的细胞挤出通过调查这一途径分叉从 凋亡途径我们还将确定下游的细胞外脂质信号， 挤压环的形成，因为我们认为这个信号可能提供了一个很好的分子标记， 挤出有了这些信号在手，我们将能够测试功能的挤压在潜力 从维持上皮细胞数量和功能到新机制， 肿瘤形成和启动肿瘤细胞转移。为了做到这一点，我们将延长我们的挤压 对整个斑马鱼胚胎的研究。

I have discovered a mechanism called `extrusion', by which dying cells exit the epithelium without disrupting the barrier function of the layer. Here, a cell destined to die, signals its surrounding neighboring cells to form an intercellular actomyosin ring that contracts to squeeze the dying cell out. While stimuli that induce cell death (apoptosis) activate extrusion, we have also found that apoptosis and extrusion are not interdependent. This suggests that extrusion may remove cells from the epithelium in other circumstances. Signals that promote extrusion could, therefore, be used when cells leave the epithelium during developmental differentiation or initiation of tumor cell metastasis. Because most high-grade tumors have mutations in the apoptotic pathway, mutations that block apoptosis but not extrusion could enable a tumor cell to easily exit the epithelium and initiate its metastasis to other sites. Because metastasis is generally associated with cancer lethality, we believe that understanding the signalling that drives extrusion may be of utmost importance. We will also explore if extrusion might precede and induce apoptosis in overcrowded regions during normal homeostasis as a way of regulating cell numbers. Identifying the signals that trigger extrusion will be key to understanding the physiological functions that extrusion plays. We plan to identify the signalling pathway that initiates commitment of cell extrusion by investigating where this pathway bifurcates from the apoptotic pathway. We will also identify the downstream extra-cellular lipid signal that elicits extruding ring formation, as we think that this signal might provide a good molecular marker for extrusion. With these signals in hand, we will be able to test the function of extrusion in potential processes ranging from maintaining epithelial numbers and function to novel mechanisms for tumor formation and initiating tumor cell metastasis. To do so, we will extend our extrusion studies into whole zebrafish embryos.