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Autophagy is required for proper cysteine homeostasis in pancreatic cancer through regulation of SLC7A11

Mukhopadhyay, Subhadip; Biancur, Douglas E; Parker, Seth J; Yamamoto, Keisuke; Banh, Robert S; Paulo, Joao A; Mancias, Joseph D; Kimmelman, Alec C
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest forms of cancer and is highly refractory to current therapies. We had previously shown that PDAC can utilize its high levels of basal autophagy to support its metabolism and maintain tumor growth. Consistent with the importance of autophagy in PDAC, autophagy inhibition significantly enhances response of PDAC patients to chemotherapy in two randomized clinical trials. However, the specific metabolite(s) that autophagy provides to support PDAC growth is not yet known. In this study, we demonstrate that under nutrient-replete conditions, loss of autophagy in PDAC leads to a relatively restricted impairment of amino acid pools, with cysteine levels showing a significant drop. Additionally, we made the striking discovery that autophagy is critical for the proper membrane localization of the cystine transporter SLC7A11. Mechanistically, autophagy impairment results in the loss of SLC7A11 on the plasma membrane and increases its localization at the lysosome in an mTORC2-dependent manner. Our results demonstrate a critical link between autophagy and cysteine metabolism and provide mechanistic insights into how targeting autophagy can cause metabolic dysregulation in PDAC.
PMID: 33531365
ISSN: 1091-6490
CID: 4776332

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)

Klionsky, Daniel J; Abdel-Aziz, Amal Kamal; Abdelfatah, Sara; Abdellatif, Mahmoud; Abdoli, Asghar; Abel, Steffen; Abeliovich, Hagai; Abildgaard, Marie H; Abudu, Yakubu Princely; Acevedo-Arozena, Abraham; Adamopoulos, Iannis E; Adeli, Khosrow; Adolph, Timon E; Adornetto, Annagrazia; Aflaki, Elma; Agam, Galila; Agarwal, Anupam; Aggarwal, Bharat B; Agnello, Maria; Agostinis, Patrizia; Agrewala, Javed N; Agrotis, Alexander; Aguilar, Patricia V; Ahmad, S Tariq; Ahmed, Zubair M; Ahumada-Castro, Ulises; Aits, Sonja; Aizawa, Shu; Akkoc, Yunus; Akoumianaki, Tonia; Akpinar, Hafize Aysin; Al-Abd, Ahmed M; Al-Akra, Lina; Al-Gharaibeh, Abeer; Alaoui-Jamali, Moulay A; Alberti, Simon; Alcocer-Gómez, Elísabet; Alessandri, Cristiano; Ali, Muhammad; Alim Al-Bari, M Abdul; Aliwaini, Saeb; Alizadeh, Javad; Almacellas, Eugènia; Almasan, Alexandru; Alonso, Alicia; Alonso, Guillermo D; Altan-Bonnet, Nihal; Altieri, Dario C; Álvarez, Élida M C; Alves, Sara; Alves da Costa, Cristine; Alzaharna, Mazen M; Amadio, Marialaura; Amantini, Consuelo; Amaral, Cristina; Ambrosio, Susanna; Amer, Amal O; Ammanathan, Veena; An, Zhenyi; Andersen, Stig U; Andrabi, Shaida A; Andrade-Silva, Magaiver; Andres, Allen M; Angelini, Sabrina; Ann, David; Anozie, Uche C; Ansari, Mohammad Y; Antas, Pedro; Antebi, Adam; Antón, Zuriñe; Anwar, Tahira; Apetoh, Lionel; Apostolova, Nadezda; Araki, Toshiyuki; Araki, Yasuhiro; Arasaki, Kohei; Araújo, Wagner L; Araya, Jun; Arden, Catherine; Arévalo, Maria-Angeles; Arguelles, Sandro; Arias, Esperanza; Arikkath, Jyothi; Arimoto, Hirokazu; Ariosa, Aileen R; Armstrong-James, Darius; Arnauné-Pelloquin, Laetitia; Aroca, Angeles; Arroyo, Daniela S; Arsov, Ivica; Artero, Rubén; Asaro, Dalia Maria Lucia; Aschner, Michael; Ashrafizadeh, Milad; Ashur-Fabian, Osnat; Atanasov, Atanas G; Au, Alicia K; Auberger, Patrick; Auner, Holger W; Aurelian, Laure; Autelli, Riccardo; Avagliano, Laura; Ávalos, Yenniffer; Aveic, Sanja; Aveleira, Célia Alexandra; Avin-Wittenberg, Tamar; Aydin, Yucel; Ayton, Scott; Ayyadevara, Srinivas; Azzopardi, Maria; Baba, Misuzu; Backer, Jonathan M; Backues, Steven K; Bae, Dong-Hun; Bae, Ok-Nam; Bae, Soo Han; Baehrecke, Eric H; Baek, Ahruem; Baek, Seung-Hoon; Baek, Sung Hee; Bagetta, Giacinto; Bagniewska-Zadworna, Agnieszka; Bai, Hua; Bai, Jie; Bai, Xiyuan; Bai, Yidong; Bairagi, Nandadulal; Baksi, Shounak; Balbi, Teresa; Baldari, Cosima T; Balduini, Walter; Ballabio, Andrea; Ballester, Maria; Balazadeh, Salma; Balzan, Rena; Bandopadhyay, Rina; Banerjee, Sreeparna; Banerjee, Sulagna; Bánréti, Ágnes; Bao, Yan; Baptista, Mauricio S; Baracca, Alessandra; Barbati, Cristiana; Bargiela, Ariadna; Barilà, Daniela; Barlow, Peter G; Barmada, Sami J; Barreiro, Esther; Barreto, George E; Bartek, Jiri; Bartel, Bonnie; Bartolome, Alberto; Barve, Gaurav R; Basagoudanavar, Suresh H; Bassham, Diane C; Bast, Robert C; Basu, Alakananda; Batoko, Henri; Batten, Isabella; Baulieu, Etienne E; Baumgarner, Bradley L; Bayry, Jagadeesh; Beale, Rupert; Beau, Isabelle; Beaumatin, Florian; Bechara, Luiz R G; Beck, George R; Beers, Michael F; Begun, Jakob; Behrends, Christian; Behrens, Georg M N; Bei, Roberto; Bejarano, Eloy; Bel, Shai; Behl, Christian; Belaid, Amine; Belgareh-Touzé, Naïma; Bellarosa, Cristina; Belleudi, Francesca; Belló Pérez, Melissa; Bello-Morales, Raquel; Beltran, Jackeline Soares de Oliveira; Beltran, Sebastián; Benbrook, Doris Mangiaracina; Bendorius, Mykolas; Benitez, Bruno A; Benito-Cuesta, Irene; Bensalem, Julien; Berchtold, Martin W; Berezowska, Sabina; Bergamaschi, Daniele; Bergami, Matteo; Bergmann, Andreas; Berliocchi, Laura; Berlioz-Torrent, Clarisse; Bernard, Amélie; Berthoux, Lionel; Besirli, Cagri G; Besteiro, Sebastien; Betin, Virginie M; Beyaert, Rudi; Bezbradica, Jelena S; Bhaskar, Kiran; Bhatia-Kissova, Ingrid; Bhattacharya, Resham; Bhattacharya, Sujoy; Bhattacharyya, Shalmoli; Bhuiyan, Md Shenuarin; Bhutia, Sujit Kumar; Bi, Lanrong; Bi, Xiaolin; Biden, Trevor J; Bijian, Krikor; Billes, Viktor A; Binart, Nadine; Bincoletto, Claudia; Birgisdottir, Asa B; Bjorkoy, Geir; Blanco, Gonzalo; Blas-Garcia, Ana; Blasiak, Janusz; Blomgran, Robert; Blomgren, Klas; Blum, Janice S; Boada-Romero, Emilio; Boban, Mirta; Boesze-Battaglia, Kathleen; Boeuf, Philippe; Boland, Barry; Bomont, Pascale; Bonaldo, Paolo; Bonam, Srinivasa Reddy; Bonfili, Laura; Bonifacino, Juan S; Boone, Brian A; Bootman, Martin D; Bordi, Matteo; Borner, Christoph; Bornhauser, Beat C; Borthakur, Gautam; Bosch, Jürgen; Bose, Santanu; Botana, Luis M; Botas, Juan; Boulanger, Chantal M; Boulton, Michael E; Bourdenx, Mathieu; Bourgeois, Benjamin; Bourke, Nollaig M; Bousquet, Guilhem; Boya, Patricia; Bozhkov, Peter V; Bozi, Luiz H M; Bozkurt, Tolga O; Brackney, Doug E; Brandts, Christian H; Braun, Ralf J; Braus, Gerhard H; Bravo-Sagua, Roberto; Bravo-San Pedro, José M; Brest, Patrick; Bringer, Marie-Agnès; Briones-Herrera, Alfredo; Broaddus, V Courtney; Brodersen, Peter; Brodsky, Jeffrey L; Brody, Steven L; Bronson, Paola G; Bronstein, Jeff M; Brown, Carolyn N; Brown, Rhoderick E; Brum, Patricia C; Brumell, John H; Brunetti-Pierri, Nicola; Bruno, Daniele; Bryson-Richardson, Robert J; Bucci, Cecilia; Buchrieser, Carmen; Bueno, Marta; Buitrago-Molina, Laura Elisa; Buraschi, Simone; Buch, Shilpa; Buchan, J Ross; Buckingham, Erin M; Budak, Hikmet; Budini, Mauricio; Bultynck, Geert; Burada, Florin; Burgoyne, Joseph R; Burón, M Isabel; Bustos, Victor; Büttner, Sabrina; Butturini, Elena; Byrd, Aaron; Cabas, Isabel; Cabrera-Benitez, Sandra; Cadwell, Ken; Cai, Jingjing; Cai, Lu; Cai, Qian; Cairó, Montserrat; Calbet, Jose A; Caldwell, Guy A; Caldwell, Kim A; Call, Jarrod A; Calvani, Riccardo; Calvo, Ana C; Calvo-Rubio Barrera, Miguel; Camara, Niels Os; Camonis, Jacques H; Camougrand, Nadine; Campanella, Michelangelo; Campbell, Edward M; Campbell-Valois, François-Xavier; Campello, Silvia; Campesi, Ilaria; Campos, Juliane C; Camuzard, Olivier; Cancino, Jorge; Candido de Almeida, Danilo; Canesi, Laura; Caniggia, Isabella; Canonico, Barbara; Cantí, Carles; Cao, Bin; Caraglia, Michele; Caramés, Beatriz; Carchman, Evie H; Cardenal-Muñoz, Elena; Cardenas, Cesar; Cardenas, Luis; Cardoso, Sandra M; Carew, Jennifer S; Carle, Georges F; Carleton, Gillian; Carloni, Silvia; Carmona-Gutierrez, Didac; Carneiro, Leticia A; Carnevali, Oliana; Carosi, Julian M; Carra, Serena; Carrier, Alice; Carrier, Lucie; Carroll, Bernadette; Carter, A Brent; Carvalho, Andreia Neves; Casanova, Magali; Casas, Caty; Casas, Josefina; Cassioli, Chiara; Castillo, Eliseo F; Castillo, Karen; Castillo-Lluva, Sonia; Castoldi, Francesca; Castori, Marco; Castro, Ariel F; Castro-Caldas, Margarida; Castro-Hernandez, Javier; Castro-Obregon, Susana; Catz, Sergio D; Cavadas, Claudia; Cavaliere, Federica; Cavallini, Gabriella; Cavinato, Maria; Cayuela, Maria L; Cebollada Rica, Paula; Cecarini, Valentina; Cecconi, Francesco; Cechowska-Pasko, Marzanna; Cenci, Simone; Ceperuelo-Mallafré, Victòria; Cerqueira, João J; Cerutti, Janete M; Cervia, Davide; Cetintas, Vildan Bozok; Cetrullo, Silvia; Chae, Han-Jung; Chagin, Andrei S; Chai, Chee-Yin; Chakrabarti, Gopal; Chakrabarti, Oishee; Chakraborty, Tapas; Chakraborty, Trinad; Chami, Mounia; Chamilos, Georgios; Chan, David W; Chan, Edmond Y W; Chan, Edward D; Chan, H Y Edwin; Chan, Helen H; Chan, Hung; Chan, Matthew T V; Chan, Yau Sang; Chandra, Partha K; Chang, Chih-Peng; Chang, Chunmei; Chang, Hao-Chun; Chang, Kai; Chao, Jie; Chapman, Tracey; Charlet-Berguerand, Nicolas; Chatterjee, Samrat; Chaube, Shail K; Chaudhary, Anu; Chauhan, Santosh; Chaum, Edward; Checler, Frédéric; Cheetham, Michael E; Chen, Chang-Shi; Chen, Guang-Chao; Chen, Jian-Fu; Chen, Liam L; Chen, Leilei; Chen, Lin; Chen, Mingliang; Chen, Mu-Kuan; Chen, Ning; Chen, Quan; Chen, Ruey-Hwa; Chen, Shi; Chen, Wei; Chen, Weiqiang; Chen, Xin-Ming; Chen, Xiong-Wen; Chen, Xu; Chen, Yan; Chen, Ye-Guang; Chen, Yingyu; Chen, Yongqiang; Chen, Yu-Jen; Chen, Yue-Qin; Chen, Zhefan Stephen; Chen, Zhi; Chen, Zhi-Hua; Chen, Zhijian J; Chen, Zhixiang; Cheng, Hanhua; Cheng, Jun; Cheng, Shi-Yuan; Cheng, Wei; Cheng, Xiaodong; Cheng, Xiu-Tang; Cheng, Yiyun; Cheng, Zhiyong; Chen, Zhong; Cheong, Heesun; Cheong, Jit Kong; Chernyak, Boris V; Cherry, Sara; Cheung, Chi Fai Randy; Cheung, Chun Hei Antonio; Cheung, King-Ho; Chevet, Eric; Chi, Richard J; Chiang, Alan Kwok Shing; Chiaradonna, Ferdinando; Chiarelli, Roberto; Chiariello, Mario; Chica, Nathalia; Chiocca, Susanna; Chiong, Mario; Chiou, Shih-Hwa; Chiramel, Abhilash I; Chiurchiù, Valerio; Cho, Dong-Hyung; Choe, Seong-Kyu; Choi, Augustine M K; Choi, Mary E; Choudhury, Kamalika Roy; Chow, Norman S; Chu, Charleen T; Chua, Jason P; Chua, John Jia En; Chung, Hyewon; Chung, Kin Pan; Chung, Seockhoon; Chung, So-Hyang; Chung, Yuen-Li; Cianfanelli, Valentina; Ciechomska, Iwona A; Cifuentes, Mariana; Cinque, Laura; Cirak, Sebahattin; Cirone, Mara; Clague, Michael J; Clarke, Robert; Clementi, Emilio; Coccia, Eliana M; Codogno, Patrice; Cohen, Ehud; Cohen, Mickael M; Colasanti, Tania; Colasuonno, Fiorella; Colbert, Robert A; Colell, Anna; ÄŒolić, Miodrag; Coll, Nuria S; Collins, Mark O; Colombo, María I; Colón-Ramos, Daniel A; Combaret, Lydie; Comincini, Sergio; Cominetti, Márcia R; Consiglio, Antonella; Conte, Andrea; Conti, Fabrizio; Contu, Viorica Raluca; Cookson, Mark R; Coombs, Kevin M; Coppens, Isabelle; Corasaniti, Maria Tiziana; Corkery, Dale P; Cordes, Nils; Cortese, Katia; Costa, Maria do Carmo; Costantino, Sarah; Costelli, Paola; Coto-Montes, Ana; Crack, Peter J; Crespo, Jose L; Criollo, Alfredo; Crippa, Valeria; Cristofani, Riccardo; Csizmadia, Tamas; Cuadrado, Antonio; Cui, Bing; Cui, Jun; Cui, Yixian; Cui, Yong; Culetto, Emmanuel; Cumino, Andrea C; Cybulsky, Andrey V; Czaja, Mark J; Czuczwar, Stanislaw J; D'Adamo, Stefania; D'Amelio, Marcello; D'Arcangelo, Daniela; D'Lugos, Andrew C; D'Orazi, Gabriella; da Silva, James A; Dafsari, Hormos Salimi; Dagda, Ruben K; Dagdas, Yasin; Daglia, Maria; Dai, Xiaoxia; Dai, Yun; Dai, Yuyuan; Dal Col, Jessica; Dalhaimer, Paul; Dalla Valle, Luisa; Dallenga, Tobias; Dalmasso, Guillaume; Damme, Markus; Dando, Ilaria; Dantuma, Nico P; Darling, April L; Das, Hiranmoy; Dasarathy, Srinivasan; Dasari, Santosh K; Dash, Srikanta; Daumke, Oliver; Dauphinee, Adrian N; Davies, Jeffrey S; Dávila, Valeria A; Davis, Roger J; Davis, Tanja; Dayalan Naidu, Sharadha; De Amicis, Francesca; De Bosscher, Karolien; De Felice, Francesca; De Franceschi, Lucia; De Leonibus, Chiara; de Mattos Barbosa, Mayara G; De Meyer, Guido R Y; De Milito, Angelo; De Nunzio, Cosimo; De Palma, Clara; De Santi, Mauro; De Virgilio, Claudio; De Zio, Daniela; Debnath, Jayanta; DeBosch, Brian J; Decuypere, Jean-Paul; Deehan, Mark A; Deflorian, Gianluca; DeGregori, James; Dehay, Benjamin; Del Rio, Gabriel; Delaney, Joe R; Delbridge, Lea M D; Delorme-Axford, Elizabeth; Delpino, M Victoria; Demarchi, Francesca; Dembitz, Vilma; Demers, Nicholas D; Deng, Hongbin; Deng, Zhiqiang; Dengjel, Joern; Dent, Paul; Denton, Donna; DePamphilis, Melvin L; Der, Channing J; Deretic, Vojo; Descoteaux, Albert; Devis, Laura; Devkota, Sushil; Devuyst, Olivier; Dewson, Grant; Dharmasivam, Mahendiran; Dhiman, Rohan; di Bernardo, Diego; Di Cristina, Manlio; Di Domenico, Fabio; Di Fazio, Pietro; Di Fonzo, Alessio; Di Guardo, Giovanni; Di Guglielmo, Gianni M; Di Leo, Luca; Di Malta, Chiara; Di Nardo, Alessia; Di Rienzo, Martina; Di Sano, Federica; Diallinas, George; Diao, Jiajie; Diaz-Araya, Guillermo; Díaz-Laviada, Inés; Dickinson, Jared M; Diederich, Marc; Dieudé, Mélanie; Dikic, Ivan; Ding, Shiping; Ding, Wen-Xing; Dini, Luciana; Dinić, Jelena; Dinic, Miroslav; Dinkova-Kostova, Albena T; Dionne, Marc S; Distler, Jörg H W; Diwan, Abhinav; Dixon, Ian M C; Djavaheri-Mergny, Mojgan; Dobrinski, Ina; Dobrovinskaya, Oxana; Dobrowolski, Radek; Dobson, Renwick C J; Đokić, Jelena; Dokmeci Emre, Serap; Donadelli, Massimo; Dong, Bo; Dong, Xiaonan; Dong, Zhiwu; Dorn Ii, Gerald W; Dotsch, Volker; Dou, Huan; Dou, Juan; Dowaidar, Moataz; Dridi, Sami; Drucker, Liat; Du, Ailian; Du, Caigan; Du, Guangwei; Du, Hai-Ning; Du, Li-Lin; du Toit, André; Duan, Shao-Bin; Duan, Xiaoqiong; Duarte, Sónia P; Dubrovska, Anna; Dunlop, Elaine A; Dupont, Nicolas; Durán, Raúl V; Dwarakanath, Bilikere S; Dyshlovoy, Sergey A; Ebrahimi-Fakhari, Darius; Eckhart, Leopold; Edelstein, Charles L; Efferth, Thomas; Eftekharpour, Eftekhar; Eichinger, Ludwig; Eid, Nabil; Eisenberg, Tobias; Eissa, N Tony; Eissa, Sanaa; Ejarque, Miriam; El Andaloussi, Abdeljabar; El-Hage, Nazira; El-Naggar, Shahenda; Eleuteri, Anna Maria; El-Shafey, Eman S; Elgendy, Mohamed; Eliopoulos, Aristides G; Elizalde, María M; Elks, Philip M; Elsasser, Hans-Peter; Elsherbiny, Eslam S; Emerling, Brooke M; Emre, N C Tolga; Eng, Christina H; Engedal, Nikolai; Engelbrecht, Anna-Mart; Engelsen, Agnete S T; Enserink, Jorrit M; Escalante, Ricardo; Esclatine, Audrey; Escobar-Henriques, Mafalda; Eskelinen, Eeva-Liisa; Espert, Lucile; Eusebio, Makandjou-Ola; Fabrias, Gemma; Fabrizi, Cinzia; Facchiano, Antonio; Facchiano, Francesco; Fadeel, Bengt; Fader, Claudio; Faesen, Alex C; Fairlie, W Douglas; Falcó, Alberto; Falkenburger, Bjorn H; Fan, Daping; Fan, Jie; Fan, Yanbo; Fang, Evandro F; Fang, Yanshan; Fang, Yognqi; Fanto, Manolis; Farfel-Becker, Tamar; Faure, Mathias; Fazeli, Gholamreza; Fedele, Anthony O; Feldman, Arthur M; Feng, Du; Feng, Jiachun; Feng, Lifeng; Feng, Yibin; Feng, Yuchen; Feng, Wei; Fenz Araujo, Thais; Ferguson, Thomas A; Fernández, Álvaro F; Fernandez-Checa, Jose C; Fernández-Veledo, Sonia; Fernie, Alisdair R; Ferrante, Anthony W; Ferraresi, Alessandra; Ferrari, Merari F; Ferreira, Julio C B; Ferro-Novick, Susan; Figueras, Antonio; Filadi, Riccardo; Filigheddu, Nicoletta; Filippi-Chiela, Eduardo; Filomeni, Giuseppe; Fimia, Gian Maria; Fineschi, Vittorio; Finetti, Francesca; Finkbeiner, Steven; Fisher, Edward A; Fisher, Paul B; Flamigni, Flavio; Fliesler, Steven J; Flo, Trude H; Florance, Ida; Florey, Oliver; Florio, Tullio; Fodor, Erika; Follo, Carlo; Fon, Edward A; Forlino, Antonella; Fornai, Francesco; Fortini, Paola; Fracassi, Anna; Fraldi, Alessandro; Franco, Brunella; Franco, Rodrigo; Franconi, Flavia; Frankel, Lisa B; Friedman, Scott L; Fröhlich, Leopold F; Frühbeck, Gema; Fuentes, Jose M; Fujiki, Yukio; Fujita, Naonobu; Fujiwara, Yuuki; Fukuda, Mitsunori; Fulda, Simone; Furic, Luc; Furuya, Norihiko; Fusco, Carmela; Gack, Michaela U; Gaffke, Lidia; Galadari, Sehamuddin; Galasso, Alessia; Galindo, Maria F; Gallolu Kankanamalage, Sachith; Galluzzi, Lorenzo; Galy, Vincent; Gammoh, Noor; Gan, Boyi; Ganley, Ian G; Gao, Feng; Gao, Hui; Gao, Minghui; Gao, Ping; Gao, Shou-Jiang; Gao, Wentao; Gao, Xiaobo; Garcera, Ana; Garcia, Maria Noé; Garcia, Verónica E; García-Del Portillo, Francisco; Garcia-Escudero, Vega; Garcia-Garcia, Aracely; Garcia-Macia, Marina; García-Moreno, Diana; Garcia-Ruiz, Carmen; García-Sanz, Patricia; Garg, Abhishek D; Gargini, Ricardo; Garofalo, Tina; Garry, Robert F; Gassen, Nils C; Gatica, Damian; Ge, Liang; Ge, Wanzhong; Geiss-Friedlander, Ruth; Gelfi, Cecilia; Genschik, Pascal; Gentle, Ian E; Gerbino, Valeria; Gerhardt, Christoph; Germain, Kyla; Germain, Marc; Gewirtz, David A; Ghasemipour Afshar, Elham; Ghavami, Saeid; Ghigo, Alessandra; Ghosh, Manosij; Giamas, Georgios; Giampietri, Claudia; Giatromanolaki, Alexandra; Gibson, Gary E; Gibson, Spencer B; Ginet, Vanessa; Giniger, Edward; Giorgi, Carlotta; Girao, Henrique; Girardin, Stephen E; Giridharan, Mridhula; Giuliano, Sandy; Giulivi, Cecilia; Giuriato, Sylvie; Giustiniani, Julien; Gluschko, Alexander; Goder, Veit; Goginashvili, Alexander; Golab, Jakub; Goldstone, David C; Golebiewska, Anna; Gomes, Luciana R; Gomez, Rodrigo; Gómez-Sánchez, Rubén; Gomez-Puerto, Maria Catalina; Gomez-Sintes, Raquel; Gong, Qingqiu; Goni, Felix M; González-Gallego, Javier; Gonzalez-Hernandez, Tomas; Gonzalez-Polo, Rosa A; Gonzalez-Reyes, Jose A; González-Rodríguez, Patricia; Goping, Ing Swie; Gorbatyuk, Marina S; Gorbunov, Nikolai V; Görgülü, Kıvanç; Gorojod, Roxana M; Gorski, Sharon M; Goruppi, Sandro; Gotor, Cecilia; Gottlieb, Roberta A; Gozes, Illana; Gozuacik, Devrim; Graef, Martin; Gräler, Markus H; Granatiero, Veronica; Grasso, Daniel; Gray, Joshua P; Green, Douglas R; Greenhough, Alexander; Gregory, Stephen L; Griffin, Edward F; Grinstaff, Mark W; Gros, Frederic; Grose, Charles; Gross, Angelina S; Gruber, Florian; Grumati, Paolo; Grune, Tilman; Gu, Xueyan; Guan, Jun-Lin; Guardia, Carlos M; Guda, Kishore; Guerra, Flora; Guerri, Consuelo; Guha, Prasun; Guillén, Carlos; Gujar, Shashi; Gukovskaya, Anna; Gukovsky, Ilya; Gunst, Jan; Günther, Andreas; Guntur, Anyonya R; Guo, Chuanyong; Guo, Chun; Guo, Hongqing; Guo, Lian-Wang; Guo, Ming; Gupta, Pawan; Gupta, Shashi Kumar; Gupta, Swapnil; Gupta, Veer Bala; Gupta, Vivek; Gustafsson, Asa B; Gutterman, David D; H B, Ranjitha; Haapasalo, Annakaisa; Haber, James E; Hać, Aleksandra; Hadano, Shinji; Hafrén, Anders J; Haidar, Mansour; Hall, Belinda S; Halldén, Gunnel; Hamacher-Brady, Anne; Hamann, Andrea; Hamasaki, Maho; Han, Weidong; Hansen, Malene; Hanson, Phyllis I; Hao, Zijian; Harada, Masaru; Harhaji-Trajkovic, Ljubica; Hariharan, Nirmala; Haroon, Nigil; Harris, James; Hasegawa, Takafumi; Hasima Nagoor, Noor; Haspel, Jeffrey A; Haucke, Volker; Hawkins, Wayne D; Hay, Bruce A; Haynes, Cole M; Hayrabedyan, Soren B; Hays, Thomas S; He, Congcong; He, Qin; He, Rong-Rong; He, You-Wen; He, Yu-Ying; Heakal, Yasser; Heberle, Alexander M; Hejtmancik, J Fielding; Helgason, Gudmundur Vignir; Henkel, Vanessa; Herb, Marc; Hergovich, Alexander; Herman-Antosiewicz, Anna; Hernández, Agustín; Hernandez, Carlos; Hernandez-Diaz, Sergio; Hernandez-Gea, Virginia; Herpin, Amaury; Herreros, Judit; Hervás, Javier H; Hesselson, Daniel; Hetz, Claudio; Heussler, Volker T; Higuchi, Yujiro; Hilfiker, Sabine; Hill, Joseph A; Hlavacek, William S; Ho, Emmanuel A; Ho, Idy H T; Ho, Philip Wing-Lok; Ho, Shu-Leong; Ho, Wan Yun; Hobbs, G Aaron; Hochstrasser, Mark; Hoet, Peter H M; Hofius, Daniel; Hofman, Paul; Höhn, Annika; Holmberg, Carina I; Hombrebueno, Jose R; Yi-Ren Hong, Chang-Won Hong; Hooper, Lora V; Hoppe, Thorsten; Horos, Rastislav; Hoshida, Yujin; Hsin, I-Lun; Hsu, Hsin-Yun; Hu, Bing; Hu, Dong; Hu, Li-Fang; Hu, Ming Chang; Hu, Ronggui; Hu, Wei; Hu, Yu-Chen; Hu, Zhuo-Wei; Hua, Fang; Hua, Jinlian; Hua, Yingqi; Huan, Chongmin; Huang, Canhua; Huang, Chuanshu; Huang, Chuanxin; Huang, Chunling; Huang, Haishan; Huang, Kun; Huang, Michael L H; Huang, Rui; Huang, Shan; Huang, Tianzhi; Huang, Xing; Huang, Yuxiang Jack; Huber, Tobias B; Hubert, Virginie; Hubner, Christian A; Hughes, Stephanie M; Hughes, William E; Humbert, Magali; Hummer, Gerhard; Hurley, James H; Hussain, Sabah; Hussain, Salik; Hussey, Patrick J; Hutabarat, Martina; Hwang, Hui-Yun; Hwang, Seungmin; Ieni, Antonio; Ikeda, Fumiyo; Imagawa, Yusuke; Imai, Yuzuru; Imbriano, Carol; Imoto, Masaya; Inman, Denise M; Inoki, Ken; Iovanna, Juan; Iozzo, Renato V; Ippolito, Giuseppe; Irazoqui, Javier E; Iribarren, Pablo; Ishaq, Mohd; Ishikawa, Makoto; Ishimwe, Nestor; Isidoro, Ciro; Ismail, Nahed; Issazadeh-Navikas, Shohreh; Itakura, Eisuke; Ito, Daisuke; Ivankovic, Davor; Ivanova, SaÅ¡ka; Iyer, Anand Krishnan V; Izquierdo, José M; Izumi, Masanori; Jäättelä, Marja; Jabir, Majid Sakhi; Jackson, William T; Jacobo-Herrera, Nadia; Jacomin, Anne-Claire; Jacquin, Elise; Jadiya, Pooja; Jaeschke, Hartmut; Jagannath, Chinnaswamy; Jakobi, Arjen J; Jakobsson, Johan; Janji, Bassam; Jansen-Dürr, Pidder; Jansson, Patric J; Jantsch, Jonathan; Januszewski, SÅ‚awomir; Jassey, Alagie; Jean, Steve; Jeltsch-David, Hélène; Jendelova, Pavla; Jenny, Andreas; Jensen, Thomas E; Jessen, Niels; Jewell, Jenna L; Ji, Jing; Jia, Lijun; Jia, Rui; Jiang, Liwen; Jiang, Qing; Jiang, Richeng; Jiang, Teng; Jiang, Xuejun; Jiang, Yu; Jimenez-Sanchez, Maria; Jin, Eun-Jung; Jin, Fengyan; Jin, Hongchuan; Jin, Li; Jin, Luqi; Jin, Meiyan; Jin, Si; Jo, Eun-Kyeong; Joffre, Carine; Johansen, Terje; Johnson, Gail V W; Johnston, Simon A; Jokitalo, Eija; Jolly, Mohit Kumar; Joosten, Leo A B; Jordan, Joaquin; Joseph, Bertrand; Ju, Dianwen; Ju, Jeong-Sun; Ju, Jingfang; Juárez, Esmeralda; Judith, Delphine; Juhász, Gábor; Jun, Youngsoo; Jung, Chang Hwa; Jung, Sung-Chul; Jung, Yong Keun; Jungbluth, Heinz; Jungverdorben, Johannes; Just, Steffen; Kaarniranta, Kai; Kaasik, Allen; Kabuta, Tomohiro; Kaganovich, Daniel; Kahana, Alon; Kain, Renate; Kajimura, Shinjo; Kalamvoki, Maria; Kalia, Manjula; Kalinowski, Danuta S; Kaludercic, Nina; Kalvari, Ioanna; Kaminska, Joanna; Kaminskyy, Vitaliy O; Kanamori, Hiromitsu; Kanasaki, Keizo; Kang, Chanhee; Kang, Rui; Kang, Sang Sun; Kaniyappan, Senthilvelrajan; Kanki, Tomotake; Kanneganti, Thirumala-Devi; Kanthasamy, Anumantha G; Kanthasamy, Arthi; Kantorow, Marc; Kapuy, Orsolya; Karamouzis, Michalis V; Karim, Md Razaul; Karmakar, Parimal; Katare, Rajesh G; Kato, Masaru; Kaufmann, Stefan H E; Kauppinen, Anu; Kaushal, Gur P; Kaushik, Susmita; Kawasaki, Kiyoshi; Kazan, Kemal; Ke, Po-Yuan; Keating, Damien J; Keber, Ursula; Kehrl, John H; Keller, Kate E; Keller, Christian W; Kemper, Jongsook Kim; Kenific, Candia M; Kepp, Oliver; Kermorgant, Stephanie; Kern, Andreas; Ketteler, Robin; Keulers, Tom G; Khalfin, Boris; Khalil, Hany; Khambu, Bilon; Khan, Shahid Y; Khandelwal, Vinoth Kumar Megraj; Khandia, Rekha; Kho, Widuri; Khobrekar, Noopur V; Khuansuwan, Sataree; Khundadze, Mukhran; Killackey, Samuel A; Kim, Dasol; Kim, Deok Ryong; Kim, Do-Hyung; Kim, Dong-Eun; Kim, Eun Young; Kim, Eun-Kyoung; Kim, Hak-Rim; Kim, Hee-Sik; Kim, Jeong Hun; Kim, Jin Kyung; Kim, Jin-Hoi; Kim, Joungmok; Kim, Ju Hwan; Kim, Keun Il; Kim, Peter K; Kim, Seong-Jun; Kimball, Scot R; Kimchi, Adi; Kimmelman, Alec C; Kimura, Tomonori; King, Matthew A; Kinghorn, Kerri J; Kinsey, Conan G; Kirkin, Vladimir; Kirshenbaum, Lorrie A; Kiselev, Sergey L; Kishi, Shuji; Kitamoto, Katsuhiko; Kitaoka, Yasushi; Kitazato, Kaio; Kitsis, Richard N; Kittler, Josef T; Kjaerulff, Ole; Klein, Peter S; Klopstock, Thomas; Klucken, Jochen; Knævelsrud, Helene; Knorr, Roland L; Ko, Ben C B; Ko, Fred; Ko, Jiunn-Liang; Kobayashi, Hotaka; Kobayashi, Satoru; Koch, Ina; Koch, Jan C; Koenig, Ulrich; Kögel, Donat; Koh, Young Ho; Koike, Masato; Kohlwein, Sepp D; Kocaturk, Nur M; Komatsu, Masaaki; König, Jeannette; Kono, Toru; Kopp, Benjamin T; Korcsmaros, Tamas; Korkmaz, Gözde; Korolchuk, Viktor I; Korsnes, Mónica Suárez; Koskela, Ali; Kota, Janaiah; Kotake, Yaichiro; Kotler, Monica L; Kou, Yanjun; Koukourakis, Michael I; Koustas, Evangelos; Kovacs, Attila L; Kovács, Tibor; Koya, Daisuke; Kozako, Tomohiro; Kraft, Claudine; Krainc, Dimitri; Krämer, Helmut; Krasnodembskaya, Anna D; Kretz-Remy, Carole; Kroemer, Guido; Ktistakis, Nicholas T; Kuchitsu, Kazuyuki; Kuenen, Sabine; Kuerschner, Lars; Kukar, Thomas; Kumar, Ajay; Kumar, Ashok; Kumar, Deepak; Kumar, Dhiraj; Kumar, Sharad; Kume, Shinji; Kumsta, Caroline; Kundu, Chanakya N; Kundu, Mondira; Kunnumakkara, Ajaikumar B; Kurgan, Lukasz; Kutateladze, Tatiana G; Kutlu, Ozlem; Kwak, SeongAe; Kwon, Ho Jeong; Kwon, Taeg Kyu; Kwon, Yong Tae; Kyrmizi, Irene; La Spada, Albert; Labonté, Patrick; Ladoire, Sylvain; Laface, Ilaria; Lafont, Frank; Lagace, Diane C; Lahiri, Vikramjit; Lai, Zhibing; Laird, Angela S; Lakkaraju, Aparna; Lamark, Trond; Lan, Sheng-Hui; Landajuela, Ane; Lane, Darius J R; Lane, Jon D; Lang, Charles H; Lange, Carsten; Langel, Ãœlo; Langer, Rupert; Lapaquette, Pierre; Laporte, Jocelyn; LaRusso, Nicholas F; Lastres-Becker, Isabel; Lau, Wilson Chun Yu; Laurie, Gordon W; Lavandero, Sergio; Law, Betty Yuen Kwan; Law, Helen Ka-Wai; Layfield, Rob; Le, Weidong; Le Stunff, Herve; Leary, Alexandre Y; Lebrun, Jean-Jacques; Leck, Lionel Y W; Leduc-Gaudet, Jean-Philippe; Lee, Changwook; Lee, Chung-Pei; Lee, Da-Hye; Lee, Edward B; Lee, Erinna F; Lee, Gyun Min; Lee, He-Jin; Lee, Heung Kyu; Lee, Jae Man; Lee, Jason S; Lee, Jin-A; Lee, Joo-Yong; Lee, Jun Hee; Lee, Michael; Lee, Min Goo; Lee, Min Jae; Lee, Myung-Shik; Lee, Sang Yoon; Lee, Seung-Jae; Lee, Stella Y; Lee, Sung Bae; Lee, Won Hee; Lee, Ying-Ray; Lee, Yong-Ho; Lee, Youngil; Lefebvre, Christophe; Legouis, Renaud; Lei, Yu L; Lei, Yuchen; Leikin, Sergey; Leitinger, Gerd; Lemus, Leticia; Leng, Shuilong; Lenoir, Olivia; Lenz, Guido; Lenz, Heinz Josef; Lenzi, Paola; León, Yolanda; Leopoldino, Andréia M; Leschczyk, Christoph; Leskelä, Stina; Letellier, Elisabeth; Leung, Chi-Ting; Leung, Po Sing; Leventhal, Jeremy S; Levine, Beth; Lewis, Patrick A; Ley, Klaus; Li, Bin; Li, Da-Qiang; Li, Jianming; Li, Jing; Li, Jiong; Li, Ke; Li, Liwu; Li, Mei; Li, Min; Li, Min; Li, Ming; Li, Mingchuan; Li, Pin-Lan; Li, Ming-Qing; Li, Qing; Li, Sheng; Li, Tiangang; Li, Wei; Li, Wenming; Li, Xue; Li, Yi-Ping; Li, Yuan; Li, Zhiqiang; Li, Zhiyong; Li, Zhiyuan; Lian, Jiqin; Liang, Chengyu; Liang, Qiangrong; Liang, Weicheng; Liang, Yongheng; Liang, YongTian; Liao, Guanghong; Liao, Lujian; Liao, Mingzhi; Liao, Yung-Feng; Librizzi, Mariangela; Lie, Pearl P Y; Lilly, Mary A; Lim, Hyunjung J; Lima, Thania R R; Limana, Federica; Lin, Chao; Lin, Chih-Wen; Lin, Dar-Shong; Lin, Fu-Cheng; Lin, Jiandie D; Lin, Kurt M; Lin, Kwang-Huei; Lin, Liang-Tzung; Lin, Pei-Hui; Lin, Qiong; Lin, Shaofeng; Lin, Su-Ju; Lin, Wenyu; Lin, Xueying; Lin, Yao-Xin; Lin, Yee-Shin; Linden, Rafael; Lindner, Paula; Ling, Shuo-Chien; Lingor, Paul; Linnemann, Amelia K; Liou, Yih-Cherng; Lipinski, Marta M; LipovÅ¡ek, SaÅ¡ka; Lira, Vitor A; Lisiak, Natalia; Liton, Paloma B; Liu, Chao; Liu, Ching-Hsuan; Liu, Chun-Feng; Liu, Cui Hua; Liu, Fang; Liu, Hao; Liu, Hsiao-Sheng; Liu, Hua-Feng; Liu, Huifang; Liu, Jia; Liu, Jing; Liu, Julia; Liu, Leyuan; Liu, Longhua; Liu, Meilian; Liu, Qin; Liu, Wei; Liu, Wende; Liu, Xiao-Hong; Liu, Xiaodong; Liu, Xingguo; Liu, Xu; Liu, Xuedong; Liu, Yanfen; Liu, Yang; Liu, Yang; Liu, Yueyang; Liu, Yule; Livingston, J Andrew; Lizard, Gerard; Lizcano, Jose M; Ljubojevic-Holzer, Senka; LLeonart, Matilde E; Llobet-Navàs, David; Llorente, Alicia; Lo, Chih Hung; Lobato-Márquez, Damián; Long, Qi; Long, Yun Chau; Loos, Ben; Loos, Julia A; López, Manuela G; López-Doménech, Guillermo; López-Guerrero, José Antonio; López-Jiménez, Ana T; López-Pérez, Óscar; López-Valero, Israel; Lorenowicz, Magdalena J; Lorente, Mar; Lorincz, Peter; Lossi, Laura; Lotersztajn, Sophie; Lovat, Penny E; Lovell, Jonathan F; Lovy, Alenka; LÅ‘w, Péter; Lu, Guang; Lu, Haocheng; Lu, Jia-Hong; Lu, Jin-Jian; Lu, Mengji; Lu, Shuyan; Luciani, Alessandro; Lucocq, John M; Ludovico, Paula; Luftig, Micah A; Luhr, Morten; Luis-Ravelo, Diego; Lum, Julian J; Luna-Dulcey, Liany; Lund, Anders H; Lund, Viktor K; Lünemann, Jan D; Lüningschrör, Patrick; Luo, Honglin; Luo, Rongcan; Luo, Shouqing; Luo, Zhi; Luparello, Claudio; Lüscher, Bernhard; Luu, Luan; Lyakhovich, Alex; Lyamzaev, Konstantin G; Lystad, Alf HÃ¥kon; Lytvynchuk, Lyubomyr; Ma, Alvin C; Ma, Changle; Ma, Mengxiao; Ma, Ning-Fang; Ma, Quan-Hong; Ma, Xinliang; Ma, Yueyun; Ma, Zhenyi; MacDougald, Ormond A; Macian, Fernando; MacIntosh, Gustavo C; MacKeigan, Jeffrey P; Macleod, Kay F; Maday, Sandra; Madeo, Frank; Madesh, Muniswamy; Madl, Tobias; Madrigal-Matute, Julio; Maeda, Akiko; Maejima, Yasuhiro; Magarinos, Marta; Mahavadi, Poornima; Maiani, Emiliano; Maiese, Kenneth; Maiti, Panchanan; Maiuri, Maria Chiara; Majello, Barbara; Major, Michael B; Makareeva, Elena; Malik, Fayaz; Mallilankaraman, Karthik; Malorni, Walter; Maloyan, Alina; Mammadova, Najiba; Man, Gene Chi Wai; Manai, Federico; Mancias, Joseph D; Mandelkow, Eva-Maria; Mandell, Michael A; Manfredi, Angelo A; Manjili, Masoud H; Manjithaya, Ravi; Manque, Patricio; Manshian, Bella B; Manzano, Raquel; Manzoni, Claudia; Mao, Kai; Marchese, Cinzia; Marchetti, Sandrine; Marconi, Anna Maria; Marcucci, Fabrizio; Mardente, Stefania; Mareninova, Olga A; Margeta, Marta; Mari, Muriel; Marinelli, Sara; Marinelli, Oliviero; Mariño, Guillermo; Mariotto, Sofia; Marshall, Richard S; Marten, Mark R; Martens, Sascha; Martin, Alexandre P J; Martin, Katie R; Martin, Sara; Martin, Shaun; Martín-Segura, Adrián; Martín-Acebes, Miguel A; Martin-Burriel, Inmaculada; Martin-Rincon, Marcos; Martin-Sanz, Paloma; Martina, José A; Martinet, Wim; Martinez, Aitor; Martinez, Ana; Martinez, Jennifer; Martinez Velazquez, Moises; Martinez-Lopez, Nuria; Martinez-Vicente, Marta; Martins, Daniel O; Martins, Joilson O; Martins, Waleska K; Martins-Marques, Tania; Marzetti, Emanuele; Masaldan, Shashank; Masclaux-Daubresse, Celine; Mashek, Douglas G; Massa, Valentina; Massieu, Lourdes; Masson, Glenn R; Masuelli, Laura; Masyuk, Anatoliy I; Masyuk, Tetyana V; Matarrese, Paola; Matheu, Ander; Matoba, Satoaki; Matsuzaki, Sachiko; Mattar, Pamela; Matte, Alessandro; Mattoscio, Domenico; Mauriz, José L; Mauthe, Mario; Mauvezin, Caroline; Maverakis, Emanual; Maycotte, Paola; Mayer, Johanna; Mazzoccoli, Gianluigi; Mazzoni, Cristina; Mazzulli, Joseph R; McCarty, Nami; McDonald, Christine; McGill, Mitchell R; McKenna, Sharon L; McLaughlin, BethAnn; McLoughlin, Fionn; McNiven, Mark A; McWilliams, Thomas G; Mechta-Grigoriou, Fatima; Medeiros, Tania Catarina; Medina, Diego L; Megeney, Lynn A; Megyeri, Klara; Mehrpour, Maryam; Mehta, Jawahar L; Meijer, Alfred J; Meijer, Annemarie H; Mejlvang, Jakob; Meléndez, Alicia; Melk, Annette; Memisoglu, Gonen; Mendes, Alexandrina F; Meng, Delong; Meng, Fei; Meng, Tian; Menna-Barreto, Rubem; Menon, Manoj B; Mercer, Carol; Mercier, Anne E; Mergny, Jean-Louis; Merighi, Adalberto; Merkley, Seth D; Merla, Giuseppe; Meske, Volker; Mestre, Ana Cecilia; Metur, Shree Padma; Meyer, Christian; Meyer, Hemmo; Mi, Wenyi; Mialet-Perez, Jeanne; Miao, Junying; Micale, Lucia; Miki, Yasuo; Milan, Enrico; Milczarek, MaÅ‚gorzata; Miller, Dana L; Miller, Samuel I; Miller, Silke; Millward, Steven W; Milosevic, Ira; Minina, Elena A; Mirzaei, Hamed; Mirzaei, Hamid Reza; Mirzaei, Mehdi; Mishra, Amit; Mishra, Nandita; Mishra, Paras Kumar; Misirkic Marjanovic, Maja; Misasi, Roberta; Misra, Amit; Misso, Gabriella; Mitchell, Claire; Mitou, Geraldine; Miura, Tetsuji; Miyamoto, Shigeki; Miyazaki, Makoto; Miyazaki, Mitsunori; Miyazaki, Taiga; Miyazawa, Keisuke; Mizushima, Noboru; Mogensen, Trine H; Mograbi, Baharia; Mohammadinejad, Reza; Mohamud, Yasir; Mohanty, Abhishek; Mohapatra, Sipra; Möhlmann, Torsten; Mohmmed, Asif; Moles, Anna; Moley, Kelle H; Molinari, Maurizio; Mollace, Vincenzo; Møller, Andreas Buch; Mollereau, Bertrand; Mollinedo, Faustino; Montagna, Costanza; 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Post, Martin; Potts, Malia B; Poulton, Joanna; Powers, Ted; Prahlad, Veena; Prajsnar, Tomasz K; Praticò, Domenico; Prencipe, Rosaria; Priault, Muriel; Proikas-Cezanne, Tassula; Promponas, Vasilis J; Proud, Christopher G; Puertollano, Rosa; Puglielli, Luigi; Pulinilkunnil, Thomas; Puri, Deepika; Puri, Rajat; Puyal, Julien; Qi, Xiaopeng; Qi, Yongmei; Qian, Wenbin; Qiang, Lei; Qiu, Yu; Quadrilatero, Joe; Quarleri, Jorge; Raben, Nina; Rabinowich, Hannah; Ragona, Debora; Ragusa, Michael J; Rahimi, Nader; Rahmati, Marveh; Raia, Valeria; Raimundo, Nuno; Rajasekaran, Namakkal-Soorappan; Ramachandra Rao, Sriganesh; Rami, Abdelhaq; Ramírez-Pardo, Ignacio; Ramsden, David B; Randow, Felix; Rangarajan, Pundi N; Ranieri, Danilo; Rao, Hai; Rao, Lang; Rao, Rekha; Rathore, Sumit; Ratnayaka, J Arjuna; Ratovitski, Edward A; Ravanan, Palaniyandi; Ravegnini, Gloria; Ray, Swapan K; Razani, Babak; Rebecca, Vito; Reggiori, Fulvio; Régnier-Vigouroux, Anne; Reichert, Andreas S; Reigada, David; Reiling, Jan H; Rein, Theo; Reipert, Siegfried; Rekha, Rokeya Sultana; Ren, Hongmei; Ren, Jun; Ren, Weichao; Renault, Tristan; Renga, Giorgia; Reue, Karen; Rewitz, Kim; Ribeiro de Andrade Ramos, Bruna; Riazuddin, S Amer; Ribeiro-Rodrigues, Teresa M; Ricci, Jean-Ehrland; Ricci, Romeo; Riccio, Victoria; Richardson, Des R; Rikihisa, Yasuko; Risbud, Makarand V; Risueño, Ruth M; Ritis, Konstantinos; Rizza, Salvatore; Rizzuto, Rosario; Roberts, Helen C; Roberts, Luke D; Robinson, Katherine J; Roccheri, Maria Carmela; Rocchi, Stephane; Rodney, George G; Rodrigues, Tiago; Rodrigues Silva, Vagner Ramon; Rodriguez, Amaia; Rodriguez-Barrueco, Ruth; Rodriguez-Henche, Nieves; Rodriguez-Rocha, Humberto; Roelofs, Jeroen; Rogers, Robert S; Rogov, Vladimir V; Rojo, Ana I; Rolka, Krzysztof; Romanello, Vanina; Romani, Luigina; Romano, Alessandra; Romano, Patricia S; Romeo-Guitart, David; Romero, Luis C; Romero, Montserrat; Roney, Joseph C; Rongo, Christopher; Roperto, Sante; Rosenfeldt, Mathias T; Rosenstiel, Philip; Rosenwald, Anne G; Roth, Kevin A; Roth, Lynn; Roth, Steven; Rouschop, Kasper M A; Roussel, Benoit D; Roux, Sophie; Rovere-Querini, Patrizia; Roy, Ajit; Rozieres, Aurore; Ruano, Diego; Rubinsztein, David C; Rubtsova, Maria P; Ruckdeschel, Klaus; Ruckenstuhl, Christoph; Rudolf, Emil; Rudolf, Rüdiger; Ruggieri, Alessandra; Ruparelia, Avnika Ashok; Rusmini, Paola; Russell, Ryan R; Russo, Gian Luigi; Russo, Maria; Russo, Rossella; Ryabaya, Oxana O; Ryan, Kevin M; Ryu, Kwon-Yul; Sabater-Arcis, Maria; Sachdev, Ulka; Sacher, Michael; Sachse, Carsten; Sadhu, Abhishek; Sadoshima, Junichi; Safren, Nathaniel; Saftig, Paul; Sagona, Antonia P; Sahay, Gaurav; Sahebkar, Amirhossein; Sahin, Mustafa; Sahin, Ozgur; Sahni, Sumit; Saito, Nayuta; Saito, Shigeru; Saito, Tsunenori; Sakai, Ryohei; Sakai, Yasuyoshi; Sakamaki, Jun-Ichi; Saksela, Kalle; Salazar, Gloria; Salazar-Degracia, Anna; Salekdeh, Ghasem H; Saluja, Ashok K; Sampaio-Marques, Belém; Sanchez, Maria Cecilia; Sanchez-Alcazar, Jose A; Sanchez-Vera, Victoria; Sancho-Shimizu, Vanessa; Sanderson, J Thomas; Sandri, Marco; Santaguida, Stefano; Santambrogio, Laura; Santana, Magda M; Santoni, Giorgio; Sanz, Alberto; Sanz, Pascual; Saran, Shweta; Sardiello, Marco; Sargeant, Timothy J; Sarin, Apurva; Sarkar, Chinmoy; Sarkar, Sovan; Sarrias, Maria-Rosa; Sarkar, Surajit; Sarmah, Dipanka Tanu; Sarparanta, Jaakko; Sathyanarayan, Aishwarya; Sathyanarayanan, Ranganayaki; Scaglione, K Matthew; Scatozza, Francesca; Schaefer, Liliana; Schafer, Zachary T; Schaible, Ulrich E; Schapira, Anthony H V; Scharl, Michael; Schatzl, Hermann M; Schein, Catherine H; Scheper, Wiep; Scheuring, David; Schiaffino, Maria Vittoria; Schiappacassi, Monica; Schindl, Rainer; Schlattner, Uwe; Schmidt, Oliver; Schmitt, Roland; Schmidt, Stephen D; Schmitz, Ingo; Schmukler, Eran; Schneider, Anja; Schneider, Bianca E; Schober, Romana; Schoijet, Alejandra C; Schott, Micah B; Schramm, Michael; Schröder, Bernd; Schuh, Kai; Schüller, Christoph; Schulze, Ryan J; Schürmanns, Lea; Schwamborn, Jens C; Schwarten, Melanie; 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Tian, Ling; Tichy, Ales; Till, Andreas; Timmerman, Vincent; Titorenko, Vladimir I; Todi, Sokol V; Todorova, Krassimira; Toivonen, Janne M; Tomaipitinca, Luana; Tomar, Dhanendra; Tomas-Zapico, Cristina; Tomić, Sergej; Tong, Benjamin Chun-Kit; Tong, Chao; Tong, Xin; Tooze, Sharon A; Torgersen, Maria L; Torii, Satoru; Torres-López, Liliana; Torriglia, Alicia; Towers, Christina G; Towns, Roberto; Toyokuni, Shinya; Trajkovic, Vladimir; Tramontano, Donatella; Tran, Quynh-Giao; Travassos, Leonardo H; Trelford, Charles B; Tremel, Shirley; Trougakos, Ioannis P; Tsao, Betty P; Tschan, Mario P; Tse, Hung-Fat; Tse, Tak Fu; Tsugawa, Hitoshi; Tsvetkov, Andrey S; Tumbarello, David A; Tumtas, Yasin; Tuñón, María J; Turcotte, Sandra; Turk, Boris; Turk, Vito; Turner, Bradley J; Tuxworth, Richard I; Tyler, Jessica K; Tyutereva, Elena V; Uchiyama, Yasuo; Ugun-Klusek, Aslihan; Uhlig, Holm H; UÅ‚amek-KozioÅ‚, Marzena; Ulasov, Ilya V; Umekawa, Midori; Ungermann, Christian; Unno, Rei; Urbe, Sylvie; Uribe-Carretero, Elisabet; Ãœstün, Suayib; Uversky, Vladimir N; Vaccari, Thomas; Vaccaro, Maria I; Vahsen, Björn F; Vakifahmetoglu-Norberg, Helin; Valdor, Rut; Valente, Maria J; Valko, Ayelén; Vallee, Richard B; Valverde, Angela M; Van den Berghe, Greet; van der Veen, Stijn; Van Kaer, Luc; van Loosdregt, Jorg; van Wijk, Sjoerd J L; Vandenberghe, Wim; Vanhorebeek, Ilse; Vannier-Santos, Marcos A; Vannini, Nicola; Vanrell, M Cristina; Vantaggiato, Chiara; Varano, Gabriele; Varela-Nieto, Isabel; Varga, Máté; Vasconcelos, M Helena; Vats, Somya; Vavvas, Demetrios G; Vega-Naredo, Ignacio; Vega-Rubin-de-Celis, Silvia; Velasco, Guillermo; Velázquez, Ariadna P; Vellai, Tibor; Vellenga, Edo; Velotti, Francesca; Verdier, Mireille; Verginis, Panayotis; Vergne, Isabelle; Verkade, Paul; Verma, Manish; Verstreken, Patrik; Vervliet, Tim; Vervoorts, Jörg; Vessoni, Alexandre T; Victor, Victor M; Vidal, Michel; Vidoni, Chiara; Vieira, Otilia V; Vierstra, Richard D; Viganó, Sonia; Vihinen, Helena; Vijayan, Vinoy; Vila, Miquel; Vilar, Marçal; 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In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
PMID: 33634751
ISSN: 1554-8635
CID: 4800842

Functional Genomics Identifies Metabolic Vulnerabilities in Pancreatic Cancer

Biancur, Douglas E; Kapner, Kevin S; Yamamoto, Keisuke; Banh, Robert S; Neggers, Jasper E; Sohn, Albert S W; Wu, Warren; Manguso, Robert T; Brown, Adam; Root, David E; Aguirre, Andrew J; Kimmelman, Alec C
Pancreatic ductal adenocarcinoma (PDA) is a deadly cancer characterized by complex metabolic adaptations that promote survival in a severely hypoxic and nutrient-limited tumor microenvironment (TME). Modeling microenvironmental influences in cell culture has been challenging, and technical limitations have hampered the comprehensive study of tumor-specific metabolism in vivo. To systematically interrogate metabolic vulnerabilities in PDA, we employed parallel CRISPR-Cas9 screens using in vivo and in vitro systems. This work revealed striking overlap of in vivo metabolic dependencies with those in vitro. Moreover, we identified that intercellular nutrient sharing can mask dependencies in pooled screens, highlighting a limitation of this approach to study tumor metabolism. Furthermore, metabolic dependencies were similar between 2D and 3D culture, although 3D culture may better model vulnerabilities that influence certain oncogenic signaling pathways. Lastly, our work demonstrates the power of genetic screening approaches to define in vivo metabolic dependencies and pathways that may have therapeutic utility.
PMID: 33152323
ISSN: 1932-7420
CID: 4656182

Multiple screening approaches reveal HDAC6 as a novel regulator of glycolytic metabolism in triple-negative breast cancer

Dowling, Catríona M; Hollinshead, Kate E R; Di Grande, Alessandra; Pritchard, Justin; Zhang, Hua; Dillon, Eugene T; Haley, Kathryn; Papadopoulos, Eleni; Mehta, Anita K; Bleach, Rachel; Lindner, Andreas U; Mooney, Brian; Düssmann, Heiko; O'Connor, Darran; Prehn, Jochen H M; Wynne, Kieran; Hemann, Michael; Bradner, James E; Kimmelman, Alec C; Guerriero, Jennifer L; Cagney, Gerard; Wong, Kwok-Kin; Letai, Anthony G; Chonghaile, Tríona Ní
Triple-negative breast cancer (TNBC) is a subtype of breast cancer without a targeted form of therapy. Unfortunately, up to 70% of patients with TNBC develop resistance to treatment. A known contributor to chemoresistance is dysfunctional mitochondrial apoptosis signaling. We set up a phenotypic small-molecule screen to reveal vulnerabilities in TNBC cells that were independent of mitochondrial apoptosis. Using a functional genetic approach, we identified that a "hit" compound, BAS-2, had a potentially similar mechanism of action to histone deacetylase inhibitors (HDAC). An in vitro HDAC inhibitor assay confirmed that the compound selectively inhibited HDAC6. Using state-of-the-art acetylome mass spectrometry, we identified glycolytic substrates of HDAC6 in TNBC cells. We confirmed that inhibition or knockout of HDAC6 reduced glycolytic metabolism both in vitro and in vivo. Through a series of unbiased screening approaches, we have identified a previously unidentified role for HDAC6 in regulating glycolytic metabolism.
PMCID:7810372
PMID: 33523897
ISSN: 2375-2548
CID: 4775962

Harnessing metabolic dependencies in pancreatic cancers [Review]

Encarnacion-Rosado, Joel; Kimmelman, Alec C.
ISI:000630643000002
ISSN: 1759-5045
CID: 4820632

Neurons Release Serine to Support mRNA Translation in Pancreatic Cancer

Banh, Robert S; Biancur, Douglas E; Yamamoto, Keisuke; Sohn, Albert S W; Walters, Beth; Kuljanin, Miljan; Gikandi, Ajami; Wang, Huamin; Mancias, Joseph D; Schneider, Robert J; Pacold, Michael E; Kimmelman, Alec C
Pancreatic ductal adenocarcinoma (PDAC) tumors have a nutrient-poor, desmoplastic, and highly innervated tumor microenvironment. Although neurons can release stimulatory factors to accelerate PDAC tumorigenesis, the metabolic contribution of peripheral axons has not been explored. We found that peripheral axons release serine (Ser) to support the growth of exogenous Ser (exSer)-dependent PDAC cells during Ser/Gly (glycine) deprivation. Ser deprivation resulted in ribosomal stalling on two of the six Ser codons, TCC and TCT, and allowed the selective translation and secretion of nerve growth factor (NGF) by PDAC cells to promote tumor innervation. Consistent with this, exSer-dependent PDAC tumors grew slower and displayed enhanced innervation in mice on a Ser/Gly-free diet. Blockade of compensatory neuronal innervation using LOXO-101, a Trk-NGF inhibitor, further decreased PDAC tumor growth. Our data indicate that axonal-cancer metabolic crosstalk is a critical adaptation to support PDAC growth in nutrient poor environments.
PMID: 33142117
ISSN: 1097-4172
CID: 4656002

Respiratory Supercomplexes Promote Mitochondrial Efficiency and Growth in Severely Hypoxic Pancreatic Cancer

Hollinshead, Kate E R; Parker, Seth J; Eapen, Vinay V; Encarnacion-Rosado, Joel; Sohn, Albert; Oncu, Tugba; Cammer, Michael; Mancias, Joseph D; Kimmelman, Alec C
Pancreatic ductal adenocarcinoma (PDAC) is characterized by extensive fibrosis and hypovascularization, resulting in significant intratumoral hypoxia (low oxygen) that contributes to its aggressiveness, therapeutic resistance, and high mortality. Despite oxygen being a fundamental requirement for many cellular and metabolic processes, and the severity of hypoxia in PDAC, the impact of oxygen deprivation on PDAC biology is poorly understood. Investigating how PDAC cells survive in the near absence of oxygen, we find that PDAC cell lines grow robustly in oxygen tensions down to 0.1%, maintaining mitochondrial morphology, membrane potential, and the oxidative metabolic activity required for the synthesis of key metabolites for proliferation. Disrupting electron transfer efficiency by targeting mitochondrial respiratory supercomplex assembly specifically affects hypoxic PDAC proliferation, metabolism, and in vivo tumor growth. Collectively, our results identify a mechanism that enables PDAC cells to thrive in severe, oxygen-limited microenvironments.
PMID: 33027658
ISSN: 2211-1247
CID: 4626982

Glutamine metabolism via glutaminase 1 in autosomal-dominant polycystic kidney disease

Soomro, Irfana; Sun, Ying; Li, Zhai; Diggs, Lonnette; Hatzivassiliou, Georgia; Thomas, Ajit G; Rais, Rana; Parker, Seth J; Slusher, Barbara S; Kimmelman, Alec C; Somlo, Stefan; Skolnik, Edward Y
PMCID:7538233
PMID: 31329939
ISSN: 1460-2385
CID: 4637312

Niche-Selective Inhibition of Pathogenic Th17 Cells by Targeting Metabolic Redundancy

Wu, Lin; Hollinshead, Kate E R; Hao, Yuhan; Au, Christy; Kroehling, Lina; Ng, Charles; Lin, Woan-Yu; Li, Dayi; Silva, Hernandez Moura; Shin, Jong; Lafaille, Juan J; Possemato, Richard; Pacold, Michael E; Papagiannakopoulos, Thales; Kimmelman, Alec C; Satija, Rahul; Littman, Dan R
Targeting glycolysis has been considered therapeutically intractable owing to its essential housekeeping role. However, the context-dependent requirement for individual glycolytic steps has not been fully explored. We show that CRISPR-mediated targeting of glycolysis in T cells in mice results in global loss of Th17 cells, whereas deficiency of the glycolytic enzyme glucose phosphate isomerase (Gpi1) selectively eliminates inflammatory encephalitogenic and colitogenic Th17 cells, without substantially affecting homeostatic microbiota-specific Th17 cells. In homeostatic Th17 cells, partial blockade of glycolysis upon Gpi1 inactivation was compensated by pentose phosphate pathway flux and increased mitochondrial respiration. In contrast, inflammatory Th17 cells experience a hypoxic microenvironment known to limit mitochondrial respiration, which is incompatible with loss of Gpi1. Our study suggests that inhibiting glycolysis by targeting Gpi1 could be an effective therapeutic strategy with minimum toxicity for Th17-mediated autoimmune diseases, and, more generally, that metabolic redundancies can be exploited for selective targeting of disease processes.
PMID: 32615085
ISSN: 1097-4172
CID: 4504552

Selective alanine transporter utilization creates a targetable metabolic niche in pancreatic cancer

Parker, Seth J; Amendola, Caroline R; Hollinshead, Kate E R; Yu, Qijia; Yamamoto, Keisuke; Encarnacion-Rosado, Joel; Rose, Rebecca E; LaRue, Madeleine M; Sohn, Albert S W; Biancur, Doug E; Paulo, Joao A; Gygi, Steven P; Jones, Drew R; Wang, Huamin; Philips, Mark R; Bar-Sagi, Dafna; Mancias, Joseph D; Kimmelman, Alec C
Pancreatic ductal adenocarcinoma (PDAC) evolves a complex microenvironment comprised of multiple cell types, including pancreatic stellate cells (PSCs). Previous studies have demonstrated that stromal supply of alanine, lipids, and nucleotides supports the metabolism, growth, and therapeutic resistance of PDAC. Here we demonstrate that alanine crosstalk between PSCs and PDAC is orchestrated by the utilization of specific transporters. PSCs utilize SLC1A4 and other transporter(s) to rapidly exchange and maintain environmental alanine concentrations. Moreover, PDAC cells upregulate SLC38A2 to supply their increased alanine demand. Cells lacking SLC38A2 fail to concentrate intracellular alanine and undergo a profound metabolic crisis resulting in markedly impaired tumor growth. Our results demonstrate that stromal-cancer metabolic niches can form through differential transporter expression, creating unique therapeutic opportunities to target metabolic demands of cancer.
PMID: 32341021
ISSN: 2159-8290
CID: 4412012