Winners versus Losers: Cell Competition in Health and Disease

赢家与输家：健康和疾病中的细胞竞争

• 批准号: BB/W017261/1
• 负责人: Pascal Meier
• 金额: $ 72.58万
• 依托单位: Institute of Cancer Research
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FW017261%2F1
• 关键词: Winners; versus; Losers; Cell; Competition

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.

细胞竞争是一种进化保守的质量控制过程，可确保在发育和衰老过程中次优（但其他可行）的次优（但其他可行）不会累积，而是被杀死和去除。如何在组织（“赢家细胞”）中持续存在或杀死（“失败者细胞”）的特定细胞是如何衡量的相对适应性差异，以及如何做出决定。这是一个重要的问题，因为细胞竞争中的缺陷会导致受损或危险细胞的持续性，最终导致器官衰竭和疾病。尽管细胞竞争通常是一种质量控制机制，但该过程也可以通过作弊细胞来利用这种过程，而癌细胞可以假装为“超级合适”，从而使它们可以以牺牲周围正常细胞为代价扩展和扩散。癌细胞之间的竞争相互作用也有助于药物治疗期间抗性克隆的出现。对细胞竞争机制的更深入了解最终可能导致针对超级竞争性癌症克隆健身景观的新方法。我们最近发现，N-甲基-D-天冬氨酸受体（NMDAR）感官适应性差异并调节上皮细胞和超级癌细胞的竞争。我们发现，该受体通过控制细胞如何与邻居进行通信来控制细胞竞争。我们发现，当被健康的正常细胞包围时，具有较低受体活性的细胞被指定为输家（高NMDAR受体活性）。在此设置下，失败者细胞（低受体活性）开始将其营养捐赠给其钳工邻居，因此以无私的方式死亡。因此，失败者细胞积极地有助于其钳工邻居的生长。我们还发现，通过在其表面上表达高水平的NMDA受体来假装具有超级拟合的癌细胞劫持了这一过程。当与此类癌细胞并置时，正常的野生型细胞现在被认为不太适合，并开始向其癌症邻居捐赠其营养，从而使其非常适合。在这里，我们将建立在发现的基础上，并旨在了解NMDAR控制健康和疾病（癌症）的分子机制。我们将使用果蝇（果蝇）的组合作为哺乳动物3D器官共培养分析和鼠类癌模型，以研究NMDAR会影响竞争行为的分子机制。我们将研究触发NMDA受体激活的信号传导途径。此外，我们将阐明NMDAR参与的下游后果，并定义获奖者和失败者的健身手指。最终目标是确定我们如何操纵癌细胞的竞争行为，以便我们可以关闭其超级竞争者的状态并将其转换为被其钳工野生型邻居杀死的超级落波器。了解细胞竞争的分子机制最终将有助于我们设计新的治疗方法，以提高组织健康，免受作弊癌细胞的影响，并在药物治疗过程中抑制癌症的进化，以避免出现致命的克隆。

项目成果

Apoptotic cell death in disease-Current understanding of the NCCD 2023.

• DOI: 10.1038/s41418-023-01153-w
• 发表时间: 2023-05
• 期刊: CELL DEATH AND DIFFERENTIATION
• 影响因子: 12.4
• 作者: Vitale, Ilio;Pietrocola, Federico;Guilbaud, Emma;Aaronson, Stuart A.;Abrams, John M.;Adam, Dieter;Agostini, Massimiliano;Agostinis, Patrizia;Alnemri, Emad S.;Altucci, Lucia;Amelio, Ivano;Andrews, David W.;Aqeilan, Rami, I;Arama, Eli;Baehrecke, Eric H.;Balachandran, Siddharth;Bano, Daniele;Barlev, Nickolai A.;Bartek, Jiri;Bazan, Nicolas G.;Becker, Christoph;Bernassola, Francesca;Bertrand, Mathieu J. M.;Bianchi, Marco E.;Blagosklonny, Mikhail V.;Blander, J. Magarian;Blandino, Giovanni;Blomgren, Klas;Borner, Christoph;Bortner, Carl D.;Bove, Pierluigi;Boya, Patricia;Brenner, Catherine;Broz, Petr;Brunner, Thomas;Damgaard, Rune Busk;Calin, George A.;Campanella, Michelangelo;Candi, Eleonora;Carbone, Michele;Carmona-Gutierrez, Didac;Cecconi, Francesco;Chan, Francis K-M;Chen, Guo-Qiang;Chen, Quan;Chen, Youhai H.;Cheng, Emily H.;Chipuk, Jerry E.;Cidlowski, John A.;Ciechanover, Aaron;Ciliberto, Gennaro;Conrad, Marcus;Cubillos-Ruiz, Juan R.;Czabotar, Peter E.;D'Angiolella, Vincenzo;Daugaard, Mads;Dawson, Ted M.;Dawson, Valina L.;De Maria, Ruggero;De Strooper, Bart;Debatin, Klaus-Michael;Deberardinis, Ralph J.;Degterev, Alexei;Del Sal, Giannino;Deshmukh, Mohanish;Di Virgilio, Francesco;Diederich, Marc;Dixon, Scott J.;Dynlacht, Brian D.;El-Deiry, Wafik S.;Elrod, John W.;Engeland, Kurt;Fimia, Gian Maria;Galassi, Claudia;Ganini, Carlo;Garcia-Saez, Ana J.;Garg, Abhishek D.;Garrido, Carmen;Gavathiotis, Evripidis;Gerlic, Motti;Ghosh, Sourav;Green, Douglas R.;Greene, Lloyd A.;Gronemeyer, Hinrich;Haecker, Georg;Hajnoczky, Gyorgy;Hardwick, J. Marie;Haupt, Ygal;He, Sudan;Heery, David M.;Hengartner, Michael O.;Hetz, Claudio;Hildeman, David A.;Ichijo, Hidenori;Inoue, Satoshi;Jaeaettelae, Marja;Janic, Ana;Joseph, Bertrand;Jost, Philipp J.;Kanneganti, Thirumala-Devi;Karin, Michael;Kashkar, Hamid;Kaufmann, Thomas;Kelly, Gemma L.;Kepp, Oliver;Kimchi, Adi;Kitsis, Richard N.;Klionsky, Daniel J.;Kluck, Ruth;Krysko, Dmitri, V;Kulms, Dagmar;Kumar, Sharad;Lavandero, Sergio;Lavrik, Inna N.;Lemasters, John J.;Liccardi, Gianmaria;Linkermann, Andreas;Lipton, Stuart A.;Lockshin, Richard A.;Lopez-Otin, Carlos;Luedde, Tom;MacFarlane, Marion;Madeo, Frank;Malorni, Walter;Manic, Gwenola;Mantovani, Roberto;Marchi, Saverio;Marine, Jean-Christophe;Martin, Seamus J.;Martinou, Jean-Claude;Mastroberardino, Pier G.;Medema, Jan Paul;Mehlen, Patrick;Meier, Pascal;Melino, Gerry;Melino, Sonia;Miao, Edward A.;Moll, Ute M.;Munoz-Pinedo, Cristina;Murphy, Daniel J.;Niklison-Chirou, Maria Victoria;Novelli, Flavia;Nunez, Gabriel;Oberst, Andrew;Ofengeim, Dimitry;Opferman, Joseph T.;Oren, Moshe;Pagano, Michele;Panaretakis, Theocharis;Pasparakis, Manolis;Penninger, Josef M.;Pentimalli, Francesca;Pereira, David M.;Pervaiz, Shazib;Peter, Marcus E.;Pinton, Paolo;Porta, Giovanni;Prehn, Jochen H. M.;Puthalakath, Hamsa;Rabinovich, Gabriel A.;Rajalingam, Krishnaraj;Ravichandran, Kodi S.;Rehm, Markus;Ricci, Jean-Ehrland;Rizzuto, Rosario;Robinson, Nirmal;Rodrigues, Cecilia M. P.;Rotblat, Barak;Rothlin, Carla, V;Rubinsztein, David C.;Rudel, Thomas;Rufini, Alessandro;Ryan, Kevin M.;Sarosiek, Kristopher A.;Sawa, Akira;Sayan, Emre;Schroder, Kate;Scorrano, Luca;Sesti, Federico;Shao, Feng;Shi, Yufang;Sica, Giuseppe S.;Silke, John;Simon, Hans-Uwe;Sistigu, Antonella;Stephanou, Anastasis;Stockwell, Brent R.;Strapazzon, Flavie;Strasser, Andreas;Sun, Liming;Sun, Erwei;Sun, Qiang;Szabadkai, Gyorgy;Tait, Stephen W. G.;Tang, Daolin;Tavernarakis, Nektarios;Troy, Carol M.;Turk, Boris;Urbano, Nicoletta;Vandenabeele, Peter;Vanden Berghe, Tom;Vander Heiden, Matthew G.;Vanderluit, Jacqueline L.;Verkhratsky, Alexei;Villunger, Andreas;von Karstedt, Silvia;Voss, Anne K.;Vousden, Karen H.;Vucic, Domagoj;Vuri, Daniela;Wagner, Erwin F.;Walczak, Henning;Wallach, David;Wang, Ruoning;Wang, Ying;Weber, Achim;Wood, Will;Yamazaki, Takahiro;Yang, Huang-Tian;Zakeri, Zahra;Zawacka-Pankau, Joanna E.;Zhang, Lin;Zhang, Haibing;Zhivotovsky, Boris;Zhou, Wenzhao;Piacentini, Mauro;Kroemer, Guido;Galluzzi, Lorenzo
• 通讯作者: Galluzzi, Lorenzo