ALDOC- and ENO2- driven glucose metabolism sustains 3D tumor spheroids growth regardless of nutrient environmental conditions: A multi-omics analysis
De Vitis, C. et al. (2023) ALDOC- and ENO2- driven glucose metabolism sustains 3D tumor spheroids growth regardless of nutrient environmental conditions: A multi-omics analysis. J. Exp. Clin. Cancer Res. 42, 69. DOI: 10.1186/s13046-023-02641-0
Metastasis is involved in forming secondary tumors, invading vascular and lymphatic vessels, and detachment from the extracellular matrix (ECM) of primary tumor sites. ECM detachment requires cancer cells to adapt to different microenvironments with nonadherent conditions. Most cancer cells, except those with stem cell properties and invasion capabilities, are unable to survive ECM detachment due to the damaging effects of integrin-mediated growth signal loss, cytoskeletal reorganization and an increase in reactive oxygen species. ECM detachment is associated with alterations to cancer cell metabolism. As such, to adapt and survive, these cells often must undergo metabolic reprogramming.
Previous studies have shown that cancer cells undergo a phenomenon called the “Warburg effect,” where even in the presence of oxygen, they use the glycolytic pathway to produce large amounts of lactate rather than producing ATP via glycolysis. Depending on the nutrient environments and tumor types, cancers can also maintain malignancy through mitochondrial oxidative phosphorylation or glutamine metabolism. Scientists hypothesize that the nutrients present in the cell’s microenvironment are what drive the metabolic phenotypes needed for different stages of metastasis.
This study utilized a multi-omics approach to evaluate the metabolic processes in the 2D to 3D transition under different nutrient conditions. Researchers cultured 3D spheroids derived from lung adenocarcinoma and breast cancer cells in nutrient-rich and nutrient-restricted environments. As a result, they found that cancer cells favor a glycolytic “metabotype” to support survival in 3D cultures, and that the glycolytic enzymes ALDOC and ENO2 are upregulated in the 2D to 3D transition of all cell lines and nutrient conditions tested. They also performed siRNA-mediated loss-of-function assays to explore the role of differentially expressed genes and proteins in lung and breast cancer cell lines. Results showed disrupting ALDOC and ENO2 enzyme activity represses lactate production and decreases the viability and size of 3D cancer spheroids. The researchers conclude that ALDOC and ENO2 could serve as potential targets to inhibit 3D tumor spheroids in lung and breast cancer cell lines under different nutrient environments. Future in vivo studies will be needed to fully understand the role of ALDOC and ENO2 in cancer metastasis, however, this mechanism shows promise as a potential therapy to hinder 3D tumor spheroid generation.
Keywords: metastasis, lung cancer, breast cancer, glucose metabolism, ALDOC, ENO2, tumor spheroids, omics
