Final Report Summary - SUPERCOMPETITORS (GENETIC AND GENOMIC STUDY OF CELL COMPETITION IN DROSOPHILA) The Secret Society of Animal Cells:Most of us live in big cities and know this by daily experience. Civic rules must be im-plemented in order to avoid extreme competitive conflicts and define appropriate social beha-viors. Recent genetic research has revealed that those social problems also occur among cells with-in the bodies of multicellular animals. In order for cells to form stable societies, they need to identify dangerous or suboptimal neighbors and eliminate them. Thanks to our ERC starting grant funded research, how groups of cells compare their relative fitness levels and decide which cell will remain in the tissue (“winner cell”) and which cell will die (“loser cell”) became increasingly clear. And the good news is that tissues resemble a meritocracy for cells, where the best cells prevail.To ensure that the best cells are selected within our bodies, nature has designed a social code which we have called “The Flower Code”, based on a gene called “flower”. Why did we call the gene “flower”?The Flower Wars.The Flower Wars (xochiyaoyotl) is the name given to the battles fought in Central America be-tween the Aztecs and their neighbours, before the arrival of the Europeans. This was a pecu-liar type of ancient war where the Aztec warriors were trained to prefer capturing their enemies in battle rather than killing them. Therefore, losers were not killed immediately, but captured, then marked as "losers" with blue paint and eventually sacrificed later during an independent ritual.Our results suggest that the gene we called “flower” works similarly during “cellular wars”. Flower is required for the selection of the best cells within a tissue or an organ, and therefore distinguishing loser cells from winner cells. As if they would be marked with different clothes, different forms of Flower tag cells as Losers (expressing the Lose forms) or winners (cells ex-pressing the ubi form) but the eventual death of the loser cells depends on the context and a cell-cell comparison on the relative levels of Lose and/or ubi expressed by neighboring cells.Due to this role, the gene was called flower after the "Flower War" between the Aztecs and their neighbors, because also there the defeated enemies were first identified as losers by painting their bodies and eventually killed (or saved) in an independent ritual.As one would expect, many insults can affect negatively the fitness of a cell, modifying the normal proliferation, physiology or metabolic rate of a cell. The “Flower Code” acts as a unifying mechanism through which the weakest cells of a population are recognized and, eventually, substituted.However, weak cells are not completely hopeless. We have also described that activation of another molecule called SPARC in loser cells protects cells against the attack of their stronger neighbors. This implies that, at this stage, the decision of whether the potential loser cell will finally be killed or not is still reversible. This intermediate state, where SPARC protects out-competed cells, may prevent the removal of valid cells that suffer only a temporary fitness deficit. However, if the differences persist or are too ample, loser cells are, nevertheless, eliminated.“Supercompetitors” and cancerThe opposite of a suboptimal cell that proliferates slowly is a cell with higher proliferation rates, which is often one of the hallmarks of cancer cells. Cancer cells could therefore abuse the cell competition mechanisms and use them to expand. In particular, the “supercompetitor hypothesis” proposes that tumors outcompete and replace the surrounding tissue. Cancer cells could abuse the “flower code” for their own benefit during invasion of healthy organs. For example, as expected if competitive interactions occur between cancer and normal cells, SPARC is upregulated at the tumour-host boundaries in several types of human cancer. The tumor-host boundary of human tumors could be considered a cellular “fighting zone”.All in all, consistent with its function as a social control that resolves conflicts among cells within cellular communities, imbalances in cell competition could have a role in the early stag-es of cancer formation, when cells start to overrun the social and developmental constraints imposed by the genome. The genetic study of cell competition will surely impact our under-standing of cancer, regeneration, stem cell biology and aging.
