Can we learn to exploit cell competition to design new therapies?
Competitive interactions occur between cells in tissues, resulting in fit cells (winners) being able to colonise tissues, as they eliminate and replace less-fit cells (losers).
We are exploring how cell competition could be harnessed for therapeutic strategies in regenerative medicine and cancer. Towards that aim, our goal is to understand the impact of cell competition on tissues and the mechanisms that cells use to compete. We combine two complementary approaches: studies in Drosophila to capture the complexity of these interactions in vivo, and projects using mammalian cell culture to follow the dynamics of cell competition, including by live imaging.
There’s never been a better time to study cell competition. A fringe phenomenon just a decade ago, it is now at the forefront of biomedical sciences. It has been implicated in cell elimination in tissue ageing in pathological conditions associated to proteotoxic stress, in determining the outcome of oncoplastic growths, in reconstituting tissue integrity after epithelial damage, in eliminating aneuploid cells in early embryos and in preventing inter-species chimaera formation, to cite a few. Our next goals are two-fold.
MECHANISMS OF CELL COMPETITION
Our lab is strongly focused on advancing our understanding of the mechanisms of cell competition. This is key to identify drug targets that can allow us to take control of how cells compete and shape tissue colonisation in disease and in therapy. We have several ongoing projects:
- Nrf2 and cell competition. Building on our previous work implicating Nrf2 in competition, we have just completed a genetic screen in Drosophila and identified several Nrf2 target genes that modulate cell competition. We are excited that this approach will lead to the identification of novel modulators of cell competition.
- Cell competition and metabolism. We also intend to explore the connection between metabolism and competition from a complementary angle, by studying the metabolic differences between winners and losers. With this approach, we hope to identify small molecule modulators of cell competition.
- Mechanical cell competition. In our earlier work, using mammalian cultured cells, we have discovered mechanical cell competition. In mechanical cell competition, loser cells have hypersensitivity to cell crowding, which is conferred by p53 activation. We are currently investigating the mechanistic basis of this process.
- How do ribosome gene loss and proteotoxic stress lead to the loser status? By investigating how ribosomal gene loss leads to the loser status, we discovered that proteotoxic stress is a leading cause of cell competition. This finding is likely relevant for ageing tissues and for the elimination of aneuploid cells in cancer, as these often present ribosome gene loss due to genomic rearrangements. Using ribosome gene mutations as well as models of proteotoxic stress-induced cell competition we are investigating the mechanistic cause of cell competition induced by proteotoxic stress.
THE ROLE OF CELL COMPETITION IN TISSUE BIOLOGY
Nowadays, it is very well established that cells in a variety of different tissues compete, but these are relatively recent discoveries. When our group was born in 2010, it was not even known whether cells in adult tissues compete and it was questioned whether cell competition might just be a Drosophila phenomenon. Over the past decade our group has actively investigated the existence and the function of cell competition in adult tissues. We showed that cell competition is operational in adult homeostatic tissues, where it can lead to the replacement of unhealthy cells with healthy cells. Specifically, we showed that, in the adult intestine of Drosophila, cell competition promotes the proliferation and self-renewal of healthy stem cells and their progeny and the progressive elimination of cells carrying disease-bearing mutations. Our lab also provided one of the first demonstrations that cell competition is a driver of tumorigenesis. We showed that, in Drosophila APC-/- driven intestinal neoplasia, tumour and host cells compete and, crucially, that mutant cells must kill surrounding host cells in order to expand. As we move to our next decade of work we are excited to continue to identify the roles and impact of cell competition in tissue physiology. For these goals we will be moving increasingly to mammalian models. Our hope is to harness vital information which can help to design strategies that can be exploited therapeutically to promote tissue colonization in regenerative medicine, or to prevent it in cancer. Here are some of our ongoing projects:
- Cell competition and p53 in epithelial repair. Using mammalian cells in culture, we are investigating the role of cell competition in epithelial repair. We have identified a physiological function for mechanical cell competition at the leading edge of migrating epithelial monolayers. We observe that a population of migratory cells, known to drive epithelial repair when monolayers are damaged, is transient and is removed from epithelia by cell competition when monolayers close. This allows epithelial sheets to reconstitute their integrity.
- Cell competition in human tissues. We aim understand how cell competition impacts cell colonisation in human (healthy and diseased) tissues, as this information is necessary to design any clinical intervention. We are beginning this work by establishing human cell cultures that recapitulate cell competition.