{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,25]],"date-time":"2026-10-25T11:52:49Z","timestamp":1792929169505,"version":"4.5.0"},"reference-count":76,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"6769","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Science"],"published-print":{"date-parts":[[2025,10,9]]},"abstract":"<jats:p>Malignant tumors are characterized by diverse metabolic stresses, including nutrient shortages, hypoxia, and buildup of metabolic by-products. To understand how cancer cells adapt to such challenges, we conducted sequential CRISPR screens to identify genes that affect cellular fitness under specific metabolic stress conditions in cell culture and to then probe their relevance in pancreatic tumors. Comparative analyses of hundreds of fitness genes revealed that cancer metabolism in vivo was shaped by bioenergetic adaptations to tumor acidosis. Mechanistically, acidosis suppressed cytoplasmic activity of extracellular signal\u2013regulated kinase (ERK), thereby preventing oncogene-induced mitochondrial fragmentation and promoting fused mitochondria. The resulting boost in mitochondrial respiration supported cancer cell adaptations to various metabolic stresses. Thus, acidosis is an environmental factor that alters energy metabolism to promote stress resilience in cancer.<\/jats:p>","DOI":"10.1126\/science.adp7603","type":"journal-article","created":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:03:28Z","timestamp":1760033008000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":56,"title":["Acidosis orchestrates adaptations of energy metabolism in tumors"],"prefix":"10.1126","volume":"390","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1339-7647","authenticated-orcid":true,"given":"Sven","family":"Groessl","sequence":"first","affiliation":[{"name":"Division of Cell Signaling and Metabolism, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, Heidelberg, Germany."},{"name":"Faculty of Biosciences, University of Heidelberg, Heidelberg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7553-4806","authenticated-orcid":true,"given":"Robert","family":"Kalis","sequence":"additional","affiliation":[{"name":"Research Institute of Molecular Pathology (IMP), Vienna BioCenter (VBC), Vienna, Austria."},{"name":"VBC PhD Program, Doctoral School of the University at Vienna and Medical University of Vienna, Vienna BioCenter (VBC), Vienna, Austria."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-4457-5726","authenticated-orcid":true,"given":"Marteinn T.","family":"Snaebjornsson","sequence":"additional","affiliation":[{"name":"Division of Tumor Metabolism and Microenvironment, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, Heidelberg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-2845-3730","authenticated-orcid":true,"given":"Leon","family":"Wambach","sequence":"additional","affiliation":[{"name":"Division of Cell Signaling and Metabolism, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, Heidelberg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-8878-829X","authenticated-orcid":true,"given":"Jakob","family":"Haider","sequence":"additional","affiliation":[{"name":"Research Institute of Molecular Pathology (IMP), Vienna BioCenter (VBC), Vienna, Austria."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian","family":"Andersch","sequence":"additional","affiliation":[{"name":"Research Institute of Molecular Pathology (IMP), Vienna BioCenter (VBC), Vienna, Austria."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8199-6422","authenticated-orcid":true,"given":"Almut","family":"Schulze","sequence":"additional","affiliation":[{"name":"Division of Tumor Metabolism and Microenvironment, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, Heidelberg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0612-770X","authenticated-orcid":true,"given":"Wilhelm","family":"Palm","sequence":"additional","affiliation":[{"name":"Division of Cell Signaling and Metabolism, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, Heidelberg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8810-6835","authenticated-orcid":true,"given":"Johannes","family":"Zuber","sequence":"additional","affiliation":[{"name":"Research Institute of Molecular Pathology (IMP), Vienna BioCenter (VBC), Vienna, Austria."},{"name":"Medical University of Vienna, Vienna BioCenter (VBC), Vienna, Austria."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2023.01.038"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.035758"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2022.01.007"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2015.12.001"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/s42255-020-0172-2"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2024.06.026"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.1600200"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-physiol-021119-034627"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature22379"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2016.01.007"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2011.12.015"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.11.025"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.09.019"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature24057"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.12.034"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.95652"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-14-2211"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-05891-2"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21670"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature07762"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.44235"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-04758-2"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature15529"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2022.110493"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2021.02.005"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.abn5637"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.03.029"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature13110"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2014.08.018"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2023.02.014"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature14898"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-020-0850-8"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1038\/s42255-020-0243-4"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/srep04927"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2016.07.003"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1186\/2049-3002-1-23"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-020-0210-7"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceb.2016.02.001"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aab4138"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-023-01163-3"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1107402108"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms4550"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncb2220"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-5793(03)00124-8"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.12.8.2245"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M607279200"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2015.01.003"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2015.01.002"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2018.06.012"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2020.10.018"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2020.10.017"},{"key":"e_1_3_2_53_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2023.09.034"},{"key":"e_1_3_2_54_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.90.3.1127"},{"key":"e_1_3_2_55_2","first-page":"1284","article-title":"Acid production in glycolysis-impaired tumors provides new insights into tumor metabolism","volume":"8","author":"Helmlinger G.","year":"2002","unstructured":"G. Helmlinger, A. Sckell, M. Dellian, N. S. Forbes, R. K. Jain, Acid production in glycolysis-impaired tumors provides new insights into tumor metabolism. Clin. Cancer Res. 8, 1284\u20131291 (2002). 11948144","journal-title":"Clin. Cancer Res."},{"key":"e_1_3_2_56_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.07.039"},{"key":"e_1_3_2_57_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M503062200"},{"key":"e_1_3_2_58_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.126915"},{"key":"e_1_3_2_59_2","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2012.500"},{"key":"e_1_3_2_60_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.07.002"},{"key":"e_1_3_2_61_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1715-0"},{"key":"e_1_3_2_62_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature13611"},{"key":"e_1_3_2_63_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2020.100143"},{"key":"e_1_3_2_64_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2022016592"},{"key":"e_1_3_2_65_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.06.017"},{"key":"e_1_3_2_66_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.943001"},{"key":"e_1_3_2_67_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng747"},{"key":"e_1_3_2_68_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0554-4"},{"key":"e_1_3_2_69_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12859-019-2849-7"},{"key":"e_1_3_2_70_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.03.052"},{"key":"e_1_3_2_71_2","doi-asserted-by":"publisher","DOI":"10.1186\/1756-0500-3-294"},{"key":"e_1_3_2_72_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2019"},{"key":"e_1_3_2_73_2","doi-asserted-by":"publisher","DOI":"10.15252\/msb.20199111"},{"key":"e_1_3_2_74_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btr597"},{"key":"e_1_3_2_75_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv007"},{"key":"e_1_3_2_76_2","doi-asserted-by":"publisher","DOI":"10.1021\/ac1021166"},{"key":"e_1_3_2_77_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-36293-4"}],"container-title":["Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/science.adp7603","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:04:48Z","timestamp":1760033088000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/science.adp7603"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,9]]},"references-count":76,"journal-issue":{"issue":"6769","published-print":{"date-parts":[[2025,10,9]]}},"alternative-id":["10.1126\/science.adp7603"],"URL":"https:\/\/doi.org\/10.1126\/science.adp7603","relation":{},"ISSN":["0036-8075","1095-9203"],"issn-type":[{"value":"0036-8075","type":"print"},{"value":"1095-9203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,9]]},"assertion":[{"value":"2024-04-10","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-04-23","order":1,"name":"revised","label":"Revised","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-07-30","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-10-09","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"eadp7603"}}