Journal Article

DKFZ-2025-02071

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Acidosis orchestrates adaptations of energy metabolism in tumors.

Groessl, S. (First author)DKFZ* ; Kalis, R. ; Snaebjörnsson, M. T.DKFZ* ; Wambach, L.DKFZ* ; Haider, J. ; Andersch, F. ; Schulze, A.DKFZ* ; Palm, W.DKFZ* ; Zuber, J.

2025
American Association for the Advancement of Science Washington, DC

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Please use a persistent id in citations: doi:10.1126/science.adp7603

Abstract: 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-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.

Keyword(s): Energy Metabolism: genetics (MeSH) ; Acidosis: metabolism (MeSH) ; Acidosis: genetics (MeSH) ; Humans (MeSH) ; Pancreatic Neoplasms: metabolism (MeSH) ; Pancreatic Neoplasms: genetics (MeSH) ; Mitochondria: metabolism (MeSH) ; Cell Line, Tumor (MeSH) ; Adaptation, Physiological: genetics (MeSH) ; Animals (MeSH) ; Mice (MeSH) ; Stress, Physiological (MeSH) ; CRISPR-Cas Systems (MeSH) ; MAP Kinase Signaling System (MeSH) ; Mitochondrial Dynamics (MeSH)

Note: ISSN 1095-9203 / DKFZ-ZMBH Alliance / #EA:A330#

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Contributing Institute(s):

1. A330 NWG Signaltransduktion und Stoffwechsel der Zelle (A330)
2. Metabolismus und Microenvironment (A410)

Research Program(s):

1. 311 - Zellbiologie und Tumorbiologie (POF4-311) (POF4-311)

Appears in the scientific report 2025

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; BIOSIS Previews ; Biological Abstracts ; Chemical Reactions ; Clarivate Analytics Master Journal List ; Current Contents - Agriculture, Biology and Environmental Sciences ; Current Contents - Life Sciences ; Current Contents - Physical, Chemical and Earth Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 50 ; Index Chemicus ; JCR ; National-Konsortium ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection ; Zoological Record

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