Dataset Information

An AMP-activated protein kinase-PGC-1α axis mediates metabolic plasticity in glioblastoma

ABSTRACT: 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.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Christian Münch

LAB HEAD: Christian Münch

PROVIDER: PXD046679 | Pride | 2025-01-19

REPOSITORIES: Pride

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Dataset's files

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			Action	DRS
	20220908_LU_LC2_MAA_BS_G55_LNT229_PGC1a_F.msf	Msf
	20220908_LU_LC2_MAA_BS_G55_LNT229_PGC1a_F.pdResult	Other
	20220908_LU_LC2_MAA_BS_G55_LNT229_PGC1a_F1.raw	Raw
	20220908_LU_LC2_MAA_BS_G55_LNT229_PGC1a_F2.raw	Raw
	20220908_LU_LC2_MAA_BS_G55_LNT229_PGC1a_F3.raw	Raw

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Publications

An AMP-activated protein kinase-PGC-1α axis mediates metabolic plasticity in glioblastoma.

Sauer Benedikt B Kueckelhaus Jan J Lorenz Nadja I NI Bozkurt Süleyman S Schulte Dorothea D Weinem Jan-Béla JB Benzarti Mohaned M Meiser Johannes J Urban Hans H Villa Giulia G Harter Patrick N PN Münch Christian C Rieger Johannes J Steinbach Joachim P JP Heiland Dieter Henrik DH Ronellenfitsch Michael W MW

Clinical and translational medicine 20241101 11

Glioblastoma, the most frequent primary malignant brain tumour in adults, is characterised by profound yet dynamic hypoxia and nutrient depletion. To sustain survival and proliferation, tumour cells are compelled to acquire metabolic plasticity with the induction of adaptive metabolic programs. Here, we interrogated the pathways necessary to enable processing of nutrients other than glucose. We employed genetic approaches (stable/inducible overexpression, CRISPR/Cas9 knockout), pharmacological i ...[more]

PMID: 39552019

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