The glutamine-aspartate metabolic tradeoff between fast growth and metabolic flexibility

Abstract

Background: Cancer cells develop selective dependencies on nutrients, creating potential opportunities for therapeutic intervention. However, how metabolic rewiring enables cancer cells to sustain proliferation while adapting to nutrient limitation remains incompletely understood.

Results: We develop a systematic framework to investigate nutrient dependencies and apply it to extracellular glutamine dependence. By measuring metabolite exchange rates across 54 cancer cell lines with different degrees of glutamine dependence, together with metabolic profiling of human stem-cell differentiation, we identify tissue-associated differences in the use of glutamine and aspartate for glutamate biosynthesis. These differences are linked to a trade-off between rapid proliferation and metabolic flexibility. Time-resolved intracellular metabolomics following glutamine withdrawal reveal a common limitation in purine biosynthesis. However, this metabolic limitation alone is insufficient to explain glutamine dependency, suggesting that additional regulatory responses to glutamine deprivation contribute to growth arrest.

Conclusions: Our study provides a systematic framework for identifying metabolic features associated with nutrient dependence and shows how established functions of glutamine, aspartate and asparagine are coordinated across diverse cancer cell types. This approach may support the mechanistic characterization and pharmacological targeting of metabolic dependencies beyond glutamine addiction.

THERAPY RESISTANCE IN MELANOMA DRIVES CILIOGENESIS AND GLUTAMINE/ASPARTATE METABOLISM DEPENDENCY
P. Lugato, R. Castro, C. Thomas +4
bioRxiv13 Oct 2026PreprintAll rights reservedFull textOncologybioRxiv
Aberrant Accumulation of Cyclin D1 Rewires Glutamine Metabolism and Generates a Metabolic Vulnerability in Squamous Cell Carcinoma
Shuyuan Zhang, Polly J. Phillips-Mason, Bartosz Mucha +9
Cancer research5 Oct 2026Peer-reviewedLicence not statedFull textOncologyPMC
Glutamine and GLS1 are key metabolic checkpoints that Limit T cell Infiltration and Function in HNSCC
S. M. Decking-Paede, I. Ugele, K. Dettmer +38
bioRxiv24 Sep 2026PreprintAll rights reservedFull textOncologybioRxiv
Tip60‐Mediated USP22 Lactylation Drives Glutamine Metabolic Reprogramming via SLC25A5 in TNBC
Fang Zhen, Hongyi Wang, Ningzhi Zhang +5
Advanced Science26 Oct 2026Peer-reviewedCC BY 4.0Full textOncologyPMC
Mitochondrial metabolic reprogramming by a glutamine antagonist radioenhancer conjugate drives pyroptosis and antitumor immunity
Rundi Song, Jinhong Li, Chaoyu Wang +6
Science Advances30 Oct 2026Peer-reviewedCC BY-NCFull textGeneral chemistry OncologySci. Adv.CrossrefEurope PMCEurope PMC+1

Cite

BibTeX RIS

BibTeX

@article{ortmayr2026glutamineaspartate,
  title = {{The glutamine-aspartate metabolic tradeoff between fast growth and metabolic flexibility}},
  author = {Karin Ortmayr and Meret Ringwald and Laurentz Schuhknecht and Sébastien Dubuis and Eleni Panoussis and Martina Blaesi and Charly Jehanno and Sarah D. Grieder and Mohamed Bentires-Alj and Moritz Mall and Mattia Zampieri},
  journal = {Genome Biology},
  year = {2026},
  month = oct,
  doi = {10.1186/s13059-026-04314-5},
  url = {https://link.springer.com/article/10.1186/s13059-026-04314-5},
  note = {CC BY 4.0},
}

RIS

TY  - JOUR
TI  - The glutamine-aspartate metabolic tradeoff between fast growth and metabolic flexibility
AU  - Karin Ortmayr
AU  - Meret Ringwald
AU  - Laurentz Schuhknecht
AU  - Sébastien Dubuis
AU  - Eleni Panoussis
AU  - Martina Blaesi
AU  - Charly Jehanno
AU  - Sarah D. Grieder
AU  - Mohamed Bentires-Alj
AU  - Moritz Mall
AU  - Mattia Zampieri
PY  - 2026
DA  - 2026/10/27
JO  - Genome Biology
DO  - 10.1186/s13059-026-04314-5
UR  - https://link.springer.com/article/10.1186/s13059-026-04314-5
AB  - Background: Cancer cells develop selective dependencies on nutrients, creating potential opportunities for therapeutic intervention. However, how metabolic rewiring enables cancer cells to sustain proliferation while adapting to nutrient limitation remains incompletely understood.  Results: We develop a systematic framework to investigate nutrient dependencies and apply it to extracellular glutamine dependence. By measuring metabolite exchange rates across 54 cancer cell lines with different degrees of glutamine dependence, together with metabolic profiling of human stem-cell differentiation, we identify tissue-associated differences in the use of glutamine and aspartate for glutamate biosynthesis. These differences are linked to a trade-off between rapid proliferation and metabolic flexibility. Time-resolved intracellular metabolomics following glutamine withdrawal reveal a common limitation in purine biosynthesis. However, this metabolic limitation alone is insufficient to explain glutamine dependency, suggesting that additional regulatory responses to glutamine deprivation contribute to growth arrest.  Conclusions: Our study provides a systematic framework for identifying metabolic features associated with nutrient dependence and shows how established functions of glutamine, aspartate and asparagine are coordinated across diverse cancer cell types. This approach may support the mechanistic characterization and pharmacological targeting of metabolic dependencies beyond glutamine addiction.
SN  - 1474-760X
ER  -

Abstract

Related

Cite