PXD046679

PXD046679 is an original dataset announced via ProteomeXchange.

Title	An AMP-activated protein kinase-PGC-1α axis mediates metabolic plasticity in glioblastoma
Description	Glioblastoma, the most frequent primary malignant brain tumor in adults, is characterized by profound yet dynamic hypoxia and nutrient depletion. To sustain survival and proliferation, tumor cells are compelled to acquire metabolic plasticity with the induction of adaptive metabolic programs. We have previously shown that the peroxisome proliferator–activated receptor γ coactivator (PGC)-1α is a key regulator of cellular respiration, proliferation and invasion in glioblastoma. Here, we interrogated the pathways necessary to enable processing of nutrients other than glucose. We employed genetic approaches (PGC-1α stable/inducible overexpression, CRISPR/Cas9 knockout), pharmacological interventions with a novel inhibitor of adenosine monophosphate kinase (AMPK) in glioblastoma cell culture systems and a proteomic approach to investigate mechanisms of metabolic plasticity towards non-glucose nutrients including galactose, fatty acids and ketone bodies. Moreover, spatially resolved multi-omic analysis integrating transcriptomics and matrix-assisted laser desorption/ionization (MALDI) was used to correlate the gene expression pattern of PGC-1α with local metabolic and genetic architecture in human glioblastoma tissue sections. A nutrient switch from glucose to galactose, ketone bodies or fatty acids triggered an initial activation of AMPK, which in turn activated PGC-1α-dependent adaptive programs towards mitochondrial metabolism. This sensor-effector mechanism was essential for metabolic plasticity with both functional AMPK and PGC-1α necessary for survival and growth of cells under non-glucose nutrient sources. In human glioblastoma tissue specimens, PGC-1α-expression correlated with non-hypoxic tumor niches defining a specific metabolic compartment. Our findings reveal a cell-intrinsic nutrient sensing and switching mechanism. The exposure to alternative fuels triggers a starvation signal that subsequently is passed on via AMPK and PGC-1α to induce adaptive programs which result in upregulation of the enzymatic machinery necessary for broader spectrum nutrient metabolism. The integration of spatially resolved transcriptomic data from human glioblastoma samples confirms the relevance of PGC-1α especially in non-hypoxic tumor regions. Thus, the AMPK-PGC-1α axis is a candidate for therapeutic inhibition in glioblastoma.
HostingRepository	PRIDE
AnnounceDate	2025-01-19
AnnouncementXML	Submission_2025-01-18_16:25:11.992.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Christian Münch
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	TMT6plex-126 reporter+balance reagent acylated residue; acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2023-11-05 17:15:38	ID requested
⏵ 1	2025-01-18 16:25:12	announced

10.1002/ctm2.70030;

Sauer B, Kueckelhaus J, Lorenz NI, Bozkurt S, Schulte D, Weinem JB, Benzarti M, Meiser J, Urban H, Villa G, Harter PN, M, ü, nch C, Rieger J, Steinbach JP, Heiland DH, Ronellenfitsch MW, axis mediates metabolic plasticity in glioblastoma. Clin Transl Med, 14(11):e70030(2024) [pubmed]

submitter keyword: AMP-Kinase, PGC-1α, PPARGC1A, hypoxia,Glioblastoma, metabolic plasticity, tumor microenvironment

Christian Münch
contact affiliation	Institute of Biochemistry II, Faculty of Medicine, Goethe University, Frankfurt am Main, Germany Frankfurt Cancer Institute, Frankfurt am Main, Germany Cardio-Pulmonary Institute, Frankfurt am Main, Germany
contact email	bozkurt@med.uni-frankfurt.de
lab head
Christian Münch
contact affiliation	Goethe University Frankfurt
contact email	ch.muench@em.uni-frankfurt.de
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2025/01/PXD046679

PRIDE project URI

• PRIDE
  1. PXD046679
     1. Label: PRIDE project
     2. Name: An AMP-activated protein kinase-PGC-1α axis mediates metabolic plasticity in glioblastoma