Winners versus Losers: Cell Competition in Health and Disease

细胞竞争是一个进化保守的质量控制过程，它确保了次优的，但在其他方面有活力的细胞在发育和衰老过程中不会积累，而是被杀死和去除。如何测量细胞组之间的相对适应性差异，以及如何决定特定细胞是否会在组织中持续存在（“赢家细胞”）或被杀死（“输家细胞”）尚未完全了解。这是一个重要的问题，因为细胞竞争的缺陷可能导致受损或危险细胞的持续存在，最终导致器官衰竭和疾病。虽然细胞竞争通常是一种质量控制机制，但这一过程也可以被欺骗癌细胞所利用，癌细胞可以假装“超级健康”，使它们以牺牲周围正常细胞为代价进行扩张和扩散。癌细胞之间的竞争性相互作用也有助于药物治疗期间耐药克隆的出现。对细胞竞争机制的深入理解可能最终导致针对超竞争性癌症克隆的适应性景观的新治疗方法。我们最近发现N-甲基-D-天冬氨酸受体（NMDAR）感知适应性差异并调节上皮细胞和超适应性癌细胞的竞争。我们发现，这种受体通过控制细胞与邻居的通信方式来控制细胞竞争。我们发现，当被健康的正常细胞（高NMDAR受体活性）包围时，受体活性较低的细胞被标记为失败者。在这种情况下，失败的细胞（低受体活性）开始将其营养素捐赠给更健康的邻居，从而以利他主义的方式死亡。因此，失败的细胞积极地促进其更健康的邻居的生长。我们还发现，这一过程被癌细胞劫持，这些癌细胞通过在其表面表达高水平的NMDA受体来假装超级健康。当与这些癌细胞并列时，正常的野生型细胞现在被认为不太适合，并开始将其营养素捐赠给癌症邻居，使它们变得超级适合。在这里，我们将以我们的发现为基础，旨在了解NMDAR控制健康和疾病（癌症）中细胞竞争的分子机制。我们将使用果蝇、果蝇以及哺乳动物3D类器官共培养试验和小鼠癌症模型的组合来研究NMDAR影响竞争行为的分子机制。我们将研究触发NMDA受体激活的信号通路。此外，我们将阐明NMDAR参与的下游后果，并定义赢家和输家的健身指纹。最终目标是确定我们如何操纵癌细胞的竞争行为，以便我们可以关闭它们的超级竞争者状态，并将它们转化为被其更适合的野生型邻居杀死的超级失败者。了解细胞竞争的分子机制将最终帮助我们设计新的治疗方法，以促进组织健康，防止欺骗癌细胞，并在药物治疗期间抑制癌症演变，以避免致命克隆的出现。

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.