Adaptive plasticity of aspartate metabolism in succinate dehydrogenase-deficient cancer cells
Sokolov, D.; Zheng, E.; Danquah, S.; Hart, M. L.; Sullivan, L. B.
Show abstract
Succinate dehydrogenase (SDH) supports cancer cell proliferation by enabling oxidative biosynthesis of the amino acid aspartate, yet SDH loss can also drive tumorigenesis. To cope with SDH loss, cancer cells can engage alternative aspartate synthesis pathways; however, the variables dictating pathway usage and adaptive mechanisms involved are incompletely understood. Here, we systematically profile the adaptation of SDH-knockout cancer cells and find that cells can adapt to SDH loss via at least two distinct mechanisms: suppression of respiratory complex I or upregulation of pyruvate carboxylase. Each route gives rise to distinct metabolic states with both shared and unique dependencies, but either route allows cells to overcome aspartate limitation, improve proliferative fitness, and mitigate pyrimidine-dependent replication stress. Overall, this work provides a comprehensive view of adaptive aspartate synthesis in SDH-deficient cancer cells, highlights a remarkable redox-constrained metabolic plasticity, and nominates potential metabolic vulnerabilities likely to be shared among SDH-deficient cancer cells.
Matching journals
The top 5 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Mitochondrial membrane potential regulates nuclear DNA methylation and gene expression through phospholipid remodeling 96%
- Intracellular Energy Controls Dynamics of Stress-induced Ribonucleoprotein Granules 96%
- A novel non-catalytic scaffolding activity of Hexokinase 2 contributes to EMT and metastasis 96%
Similar papers in this journal
Similar papers in this journal
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.