Unravelling the pathways that mediate cell competition during embryonic differentiation

在发育开始时，胚胎的细胞开始具有非常广泛的发育潜力，称为多能性。多能细胞不仅重要，因为它们将产生将形成新生生物体的所有细胞类型和组织，而且由于它们在细胞疗法中的未来临床应用以及它们在开发患者特异性“disease-in-a-dish”方法以了解人类疾病中的用途，它们对再生医学也有很大的希望。因此，了解消除异常或有缺陷的多能细胞的机制是关键。我们已经确定了一个这样的机制，称为细胞竞争。我们已经证明，在细胞竞争过程中，细胞会比较它们的相对适应性水平，那些被认为比它们的邻居适应性差的细胞会从胚胎中被淘汰。细胞竞争的一个重要含义是，细胞的扩张能力不仅决定其自身的生长，而且决定其邻居的行为。通过从胚胎干细胞库中消除次优细胞，细胞竞争确保了维持胚胎未来发育的细胞质量，以及形成生殖系（将产生下一代的细胞）。有趣的是，我们还表明，具有癌症突变的细胞可以表现得像超级竞争对手，并通过消除正常细胞来扩张。这表明，除了上述质量控制作用外，细胞竞争可能是癌细胞在组织中扩展所使用的新机制。在这里，我们将揭开细胞竞争是如何调节的。为此，我们将确定哪些是适应细胞发出消除不适应细胞信号的途径。这些实验不仅能让我们了解胚胎处理缺陷细胞的方式，还能让我们了解细胞竞争在确保衰老组织健康和防止癌细胞扩散方面的其他可能作用。

At the beginning of development, the cells of the embryo start off with a very broad developmental potential, termed pluripotency. Pluripotent cells are not only important as they will give rise to all the cell types and tissues that will form the newborn organism, but also hold great promise for regenerative medicine due to their future clinical applications in cellular therapies and their use in the development of patient specific "disease-in-a-dish" approaches to understand human diseases. It is therefore key to understand the mechanisms that eliminate abnormal or defective pluripotent cells. We have identified one such mechanism, termed cell competition. We have shown that during cell competition, cells compare their relative fitness level, and those cells that are recognised as less fit than their neighbours are eliminated from the embryo. An important implication of cell competition is that the ability of a cell to expand is not only determinant on its own growth, but also on the behaviour of its neighbours. By eliminating suboptimal cells from the embryonic stem cells pool cell competition ensures the quality of the cells that will sustain the future development of the embryo, as well as form the germline (cells that will give rise to the next generation). Interestingly, we have also shown that cells with cancer mutations can behave like super-competitors and expand by eliminating normal cells. This suggests that in addition to the above quality control role, cell competition could be a new mechanism used by cancer cells expand in the tissue. Here we will unravel how cell competition is regulated. For this we will establish which are the pathways by which fit cells signal the elimination of less-fit cells. These experiments will give us insight not only into the ways in which the embryo deals with defective cells, but will also give us insight into other possible roles of cell competition in ensuring the fitness of ageing tissues and preventing the expansion of cancer cells.