Unravelling the pathways that mediate cell competition during embryonic differentiation

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.

Ensuring that mutations are not propagated within stem cell populations is key to proper development and homeostasis. This is especially relevant when it comes to pluripotent cells, that not only can give rise to all lineages, including the germ line, but that are also of great importance to regenerative medicine. We have found that cell competition is a mechanism that ensures the fitness of the mammalian pluripotent stem cell pool. During cell competition pluripotent stem cells measure their relative fitness and those cells that are less-fit than their neighbours are eliminated (termed loser cells) and the fitter cells (winners) undergo compensatory proliferation. This implies that cells somehow measure their relative fitness levels. We do not know how cells perform this relative fitness sensing and this will be the thrust of this proposal.

P53 is a tumour suppressor mutated in about half of human cancers. In preliminary work to this proposal, we have identified that p53 levels of expression determines the competitive fitness of pluripotent stem cells. For example, cells with high p53 expression are eliminated by their neighbours and cells with null mutations in p53 eliminate the cells surrounding them. Furthermore, we have uncovered two factors acting downstream of p53 during cell competition: (i) NFkb, a transcription factor involved in the immune response that regulates the elimination of loser cells, and (ii) Atf4, a transcription factor implicated in stress responses, that regulates the behaviour of winner cells.Here we will study the roles of the pathways regulated by Nfkb and Atf4 in cell competition. Specifically, we will do two things, First, we will pursue the signalling events that induce loser cell elimination by analysing the pathways acting upstream of Nfkb. Second, as we have found that Atf4 is required in winner cells for their competitive advantage, we will study the pathways acting downstream of Atf4 that regulate cell competition