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.

细胞竞争是一个进化保守的质量控制过程，它确保次优的、但在其他方面可行的细胞不会在发育和老化过程中积累，而是被杀死和移除。如何衡量不同细胞组之间的相对适应性差异，以及如何决定某个特定细胞将在组织中存活(“赢家细胞”)还是被杀死(“输家细胞”)，目前还不完全清楚。这是一个重要的问题，因为细胞竞争中的缺陷可能会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，但这一过程也可能被作弊的癌细胞利用，这种细胞可以伪装成“超级适合”，允许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在药物治疗过程中出现耐药克隆。对细胞竞争机制的深入理解可能最终导致针对超竞争癌症克隆的适应度格局的新的治疗方法。我们最近发现，N-甲基-D-天冬氨酸受体(NMDAR)感知适应度差异，并调节上皮细胞和超适应癌细胞的竞争。我们发现，这种受体通过控制细胞与邻居的交流来控制细胞竞争。我们发现，当被健康的正常细胞包围时，受体活性较低的细胞被标记为失败者(高NMDAR受体活性)。在这种情况下，失败的细胞(低受体活性)开始将其营养物质捐赠给更健康的邻居，从而以利他主义的方式死亡。因此，失败者细胞积极地为更健康的邻居的成长做出贡献。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这种NMDA受体来假装超级适合。当与这些癌细胞并列在一起时，正常的野生型细胞现在被认为不太适合，并开始将它们的营养物质捐赠给它们的癌症邻居，使它们超级适合。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)细胞竞争的分子机制。我们将结合果蝇、果蝇以及哺乳动物3D有机化合物共培养试验和小鼠癌症模型来研究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可以如何操纵癌细胞的竞争行为，以便我们能够关闭它们的超级竞争者地位，并将它们转变为超级失败者，被更健康的野生型邻居杀死。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，以促进组织健康，保护不受欺骗的癌细胞，并在药物治疗过程中抑制癌症演变，以避免出现致命克隆。

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