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000305225 1001_ $$00000-0002-1339-7647$$aGroessl, Sven$$b0$$eFirst author
000305225 245__ $$aAcidosis orchestrates adaptations of energy metabolism in tumors.
000305225 260__ $$aWashington, DC$$bAmerican Association for the Advancement of Science$$c2025
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000305225 520__ $$aMalignant tumors are characterized by diverse metabolic stresses, including nutrient shortages, hypoxia, and buildup of metabolic by-products. To understand how cancer cells adapt to such challenges, we conducted sequential CRISPR screens to identify genes that affect cellular fitness under specific metabolic stress conditions in cell culture and to then probe their relevance in pancreatic tumors. Comparative analyses of hundreds of fitness genes revealed that cancer metabolism in vivo was shaped by bioenergetic adaptations to tumor acidosis. Mechanistically, acidosis suppressed cytoplasmic activity of extracellular signal-regulated kinase (ERK), thereby preventing oncogene-induced mitochondrial fragmentation and promoting fused mitochondria. The resulting boost in mitochondrial respiration supported cancer cell adaptations to various metabolic stresses. Thus, acidosis is an environmental factor that alters energy metabolism to promote stress resilience in cancer.
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000305225 650_2 $$2MeSH$$aEnergy Metabolism: genetics
000305225 650_2 $$2MeSH$$aAcidosis: metabolism
000305225 650_2 $$2MeSH$$aAcidosis: genetics
000305225 650_2 $$2MeSH$$aHumans
000305225 650_2 $$2MeSH$$aPancreatic Neoplasms: metabolism
000305225 650_2 $$2MeSH$$aPancreatic Neoplasms: genetics
000305225 650_2 $$2MeSH$$aMitochondria: metabolism
000305225 650_2 $$2MeSH$$aCell Line, Tumor
000305225 650_2 $$2MeSH$$aAdaptation, Physiological: genetics
000305225 650_2 $$2MeSH$$aAnimals
000305225 650_2 $$2MeSH$$aMice
000305225 650_2 $$2MeSH$$aStress, Physiological
000305225 650_2 $$2MeSH$$aCRISPR-Cas Systems
000305225 650_2 $$2MeSH$$aMAP Kinase Signaling System
000305225 650_2 $$2MeSH$$aMitochondrial Dynamics
000305225 7001_ $$00000-0001-7553-4806$$aKalis, Robert$$b1
000305225 7001_ $$0P:(DE-He78)7b7131e0870c28d432e48873d295460f$$aSnaebjörnsson, Marteinn Thor$$b2$$udkfz
000305225 7001_ $$0P:(DE-He78)b6582817d6545fa4a747fed615a87596$$aWambach, Leon$$b3$$udkfz
000305225 7001_ $$00009-0004-8878-829X$$aHaider, Jakob$$b4
000305225 7001_ $$aAndersch, Florian$$b5
000305225 7001_ $$0P:(DE-He78)94ae391f53fb9285e1b68f9930615af1$$aSchulze, Almut$$b6$$udkfz
000305225 7001_ $$0P:(DE-He78)c8525dbb77cddc5280375ea4a5e3c13e$$aPalm, Wilhelm$$b7$$udkfz
000305225 7001_ $$00000-0001-8810-6835$$aZuber, Johannes$$b8
000305225 773__ $$0PERI:(DE-600)2066996-3$$a10.1126/science.adp7603$$gVol. 390, no. 6769, p. eadp7603$$n6769$$peadp7603$$tScience$$v390$$x0036-8075$$y2025
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