Catabolism of extracellular glutathione is a driver of metastasis formation
- 1Division of Tumor Metabolism and Microenvironment, German Cancer Research Center (DKFZ) and ZMBH-DKFZ Alliance; Heidelberg, Germany
Abstract
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.
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BibTeX
@misc{vogel2026catabolism,
title = {{Catabolism of extracellular glutathione is a driver of metastasis formation}},
author = {F. C. Vogel and F. Roehrig and D. Schilling and A. B. Chaves-Filho and G. Mattavelli and M. Kraemer and J. Haenlin and A. M. Winkelkotte and V. Fournier and K. M. Al-Shami and H. Rohdjess and P. Poeller and T. Poth and C. Stange and B. Kuester and L. Wagner and V. Thewes and A. Schneeweiss and P. Lichter and L. Schlicker and M. T. Snaebjornsson and A. Riedel and A. Schulze},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.12.757337},
url = {https://www.biorxiv.org/content/10.64898/2026.10.12.757337v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Catabolism of extracellular glutathione is a driver of metastasis formation
AU - F. C. Vogel
AU - F. Roehrig
AU - D. Schilling
AU - A. B. Chaves-Filho
AU - G. Mattavelli
AU - M. Kraemer
AU - J. Haenlin
AU - A. M. Winkelkotte
AU - V. Fournier
AU - K. M. Al-Shami
AU - H. Rohdjess
AU - P. Poeller
AU - T. Poth
AU - C. Stange
AU - B. Kuester
AU - L. Wagner
AU - V. Thewes
AU - A. Schneeweiss
AU - P. Lichter
AU - L. Schlicker
AU - M. T. Snaebjornsson
AU - A. Riedel
AU - A. Schulze
PY - 2026
DA - 2026/10/12
PB - bioRxiv
DO - 10.64898/2026.10.12.757337
UR - https://www.biorxiv.org/content/10.64898/2026.10.12.757337v1
AB - 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.
ER -