Document Type
Article
Publication Date
7-2023
Keywords
Reverse Warburg effect; CAF; Tunneling nanotube; Tumor microenvironment; Bioenergetics; Tumor spheroid; ATP production
Abstract
Cancer-associated fibroblasts (CAFs) have distinct roles within the tumor microenvironment, which can impact the mode and efficacy of tumor cell migration. CAFs are known to increase invasion of less-aggressive breast cancer cells through matrix remodeling and leader–follower dynamics. Here, we demonstrate that CAFs communicate with breast cancer cells through the formation of contact-dependent tunneling nanotubes (TNTs), which allow for the exchange of cargo between cell types. CAF mitochondria are an integral cargo component and are sufficient to increase the 3D migration of cancer cells. This cargo transfer results in an increase in mitochondrial ATP production in cancer cells, whereas it has a negligible impact on glycolytic ATP production. Manually increasing mitochondrial oxidative phosphorylation (OXPHOS) by providing extra substrates for OXPHOS fails to enhance cancer cell migration unless glycolysis is maintained at a constant level. Together, these data indicate that tumor–stromal cell crosstalk via TNTs and the associated metabolic symbiosis is a finely controlled mechanism by which tumor cells co-opt their microenvironment to promote cancer progression and may become a potential therapeutic target.
Citation
Gwolas, K. F., Libring, S., Berestesky, E., Gholizadeh, S., Schwager, S. C., Frost, A. R., Gaborski, T. R., Zhang, J., & Reinhart-King, C. A. (2023). Mitochondrial Transfer from Cancer-associated Fibroblasts Increases Migration in Aggressive Breast Cancer. Journal of Cell Science, 136 (14), jcs260419. https://doi.org/10.1242/jcs.260419
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.
