Winners versus Losers: Cell Competition in Health and Disease

Cell competition is an evolutionary conserved quality control process, which ensures that suboptimal, but otherwise viable, cells do not accumulate during development and aging, but instead are killed and removed. How relative fitness disparities are measured across groups of cells, and how the decision is taken whether a particular cell will persist in the tissue ('winner cell') or is killed ('loser cell') is not completely understood.

This is an important issue as defects in cell competition can lead to the persistence of damaged or dangerous cells, ultimately leading to organ failure and disease. While cell competition generally serves as a quality control mechanism, this process can also be exploited by cheating cancer cells, which can pretend to be 'super-fit', allowing them to expand and spread at the expense of surrounding normal cells. Competitive interactions among cancer cells also contribute to the emergence of resistant clones during drug treatment.

A deeper understanding of the mechanism of cell competition may ultimately lead to new treatment approaches that target the fitness landscape of supercompetitive cancer clones.

We recently discovered that the N-methyl-D-aspartate receptor (NMDAR) senses fitness disparities and regulates competition of epithelial cells and super-fit cancer cells. We found that this receptor controls cell competition by controlling how cells communicate with their neighbours. We discovered that cells with lower receptor activity are earmarked as losers when surrounded by healthy normal cells (high NMDAR receptor activity). Under this setting the loser cell (low receptor activity) starts to donate its nutrients to its fitter neighbours, and consequently dies in an altruistic fashion. Thus, the loser cell actively contributes to the growth of its fitter neighbours. We also found that this process is hijacked by cancer cells that pretend to be super-fit by expressing high levels of this NMDA receptor on their surface. When juxtaposed to such cancer cells, normal wild-type cells are now deemed to be less fit and start to donate their nutrients to their cancer neighbours, making them super-fit.

Here, we will build on our discovery and aim to understand the molecular mechanism by which NMDAR is controlling cell competition in health and disease (cancer). We will use a combination of Drosophila, the fruit fly, as a well as mammalian 3D organoid co-culture assays and murine cancer models to study the molecular mechanism through which NMDAR influences competitive behaviour. We will study the signalling routes that trigger NMDA receptor activation. Moreover, we will elucidate the downstream consequences of NMDAR engagement and define fitness finger prints of winners and losers. The ultimate goal is to identify how we can manipulate the competitive behaviour of cancer cells so that we can switch off their supercompetitor status and convert them into superlosers that are killed by their fitter wild-type neighbours.

Understanding the molecular mechanisms of cell competition will ultimately help us to design new therapeutic approaches to boost tissue health, protect from cheating cancer cells and restrain cancer evolution during drug treatment to avoid the emergence of lethal clones.

The elimination of suboptimal or potentially dangerous cells is essential for the maintenance of tissue homeostasis and suppression of tumorigenesis during development and aging. When suboptimal, but otherwise viable cells are confronted with fitter cells in a tissue, weaker cells are often eliminated by apoptosis through a process known as cell competition. How relative fitness disparities are measured across groups of cells, and how the decision is taken whether a cell will persist in the tissue (winner) or is killed (loser) is not understood. This is an important issue, as competitive behaviour can be exploited by cells with deregulated oncogenes or tumour suppressors, which subsequently expand at the expense of their wild-type neighbours.

We discovered that the NMDA receptor (NMDAR) senses fitness disparity and regulates competition of epithelial cells and oncogenic supercompetitors. Our finding that NMDAR is involved in transmitting information about cell fitness forms the basis of this application.

Here, we will delineate the signalling routes through which glutamate and its receptor NMDAR influences life versus death decisions in competing populations. We will study how NMDAR is activated and how it influences signalling pathways that regulate metabolism, growth and death of competing cells (1). Further, we will identify fitness fingerprints of adjacent winners and losers (2). Finally, using mammalian 3D co-culture assays and a mouse models of breast cancer, we will translate our findings from Drosophila to the mammalian setting and develop novel anti-cancer treatment protocols that target the competitiveness of tumour cells, thereby converting supercompetitive tumour cells into superlosers (3).

Identification of the mechanisms of cell competition will have implications for developmental biology, regeneration biology, aging and cancer where clonal evolution in response to drug treatment frequently leads to the emergence of therapy resistant clones.