Biology subjects

Snaebjornsson, M. T.

Publications and source records attributed to Snaebjornsson, M. T..

3 recordsLinked to original sources

bioRxiv2026

Catabolism of extracellular glutathione is a driver of metastasis formation

Metastasizing cancer cells require metabolic plasticity to adapt to the microenvironment of the target organ. Analyzing metabolites in interstitial fluids, we found that the liver microenvironment is devoid of cystine but contains high concentrations of glutathione (GSH). Detailed mechanistic analysis revealed that cancer cells degrade extracellular GSH utilizing gamma-glutamyl-transferase (GGT) activity for provision of cysteine to support proliferation and prevent ferroptosis under cystine-free conditions. This was independent of system Xc- but required activity of glutamate-cysteine ligase (GCLC). GGT1 expression was associated with poor survival and upregulated in liver metastases of human breast cancer patients. Overexpression of Ggt1 in murine breast cancer cells enhanced their capacity for liver colonization and promoted lung metastases after orthotopic implantation. This identifies extracellular GSH catabolism as driver of metastasis that supports proliferation and oxidative stress resistance in metabolically challenging microenvironments.

cancer biology↗

bioRxiv2025

Genomic G quadruplexes regulate mRNA splicing

Genomic G quadruplexes (G4) are non-canonical DNA structures that regulate gene expression primarily through transcriptional control. Here, we uncover that DNA G quadruplexes are critical determinants of pre-mRNA splicing. G4s on the DNA template strand serve as recruiting elements for the RNA-binding proteins SRSF9 and WBP11 in order to facilitate productive splicing of adjacent pre-mRNAs. This process is controlled by protein arginine methyltransferase 5 (PRMT5) that releases SRSF9 and WBP11 from G4s through arginine methylation. Acyl-CoA dehydrogenase very long-chain specific (ACADVL) is a gene highly regulated by this mechanism since targeting G4 stability prevents mis-splicing and restores ACADVL protein levels. In the heart, deletion of Prmt5 recapitulates defective splicing and results in progressive cardiac failure along with loss of ACADVL in mice. Importantly, we find that Acadvl regulation plays a critical role for cardiomyopathy as restoring Acadvl expression in Prmt5 knockout mice prevents cardiac dysfunction. This study establishes an unanticipated fundamental principle by which genomic G quadruplexes act as splicing enhancers of associated pre-mRNAs, and reveals an essential role in cardiac homeostasis.

cell biology↗

bioRxiv2021

Glycolytic flux-signaling controls mouse embryo mesoderm development

How cellular metabolic state impacts cellular programs is a fundamental, unresolved question. Here we investigated how glycolytic flux impacts embryonic development, using presomitic mesoderm (PSM) patterning as the experimental model. First, we identified fructose 1,6-bisphosphate (FBP) as an in vivo sentinel metabolite that mirrors glycolytic flux within PSM cells of post-implantation mouse embryos. We found that medium-supplementation with FBP, but not with other glycolytic metabolites, such as fructose 6-phosphate and 3-phosphoglycerate, impaired mesoderm segmentation. To genetically manipulate glycolytic flux and FBP levels, we generated a mouse model enabling the conditional overexpression of dominant active, cytoplasmic Pfkfb3 (cytoPfkfb3). Overexpression of cytoPfkfb3 indeed led to increased glycolytic flux/FBP levels and caused an impairment of mesoderm segmentation, paralleled by the downregulation of Wnt-signaling, reminiscent of the effects seen upon FBP-supplementation. To probe for mechanisms underlying glycolytic flux-signaling, we performed subcellular proteome analysis and revealed that cytoPfkfb3 overexpression altered subcellular localization of certain proteins, including glycolytic enzymes, in PSM cells. Specifically, we revealed that FBP supplementation caused depletion of Pfkl and Aldoa from the nuclear-soluble fraction. Combined, we propose that FBP functions as a flux-signaling metabolite connecting glycolysis and PSM patterning, potentially through modulating subcellular protein localization.

developmental biology↗