Identifying New Targets in Cancer Metabolism and Treatment

Progress in cancer research over the past ten years has helped scientists gain a greater understanding of cancer cell metabolism and how cancer cells interact – metabolically speaking – with neighboring cells in the tumor microenvironment in order to secure the nutrients they need to proliferate.

“Learning which conversations between cancer cells and their neighbors to interrupt could potentially point us to new targets for treatments that are more effective than those in use today,” said Deepak Nagrath, associate professor, who joined the BME faculty in January 2017.

In ongoing work begun at Rice University, Nagrath takes a systems biology approach, combining a metabolic isotope tracing technique with a computational framework, together known as 13C-based metabolic flux analysis. He has conducted a number of studies to more fully understand the metabolism of cancer cells as well as their interactions with their immediate environment.

In work published in November 2016 in Cell Metabolism, Nagrath focused on glutamine, an amino acid for which many types of cancer cells have been shown to have a voracious appetite. He also focused on the related enzyme glutamine synthetase in the stroma, or the connective tissue that makes up the tumor microenvironment.

In ovarian cancer cells, Nagrath’s team found greater expression of genes that control glutamine production than in normal cells and that, when the cancer cells were put into a glutamine-deprived environment, surrounding cells known as cancer-associated fibroblasts (CAFs) began producing higher than normal levels of the amino acid.

Upon further investigation, the researchers observed an interesting dynamic between the cancer and stromal cells: The cancer cells appeared to barter with their neighbors. The cancer cells contributed two enzymes, lactate and glutamate, and in exchange, the neighboring CAFs used the enzymes to produce – and share – glutamine.

But when the team inhibited glutamine production by the neighboring CAFs using drugs or through depriving them of nutrients, the ovarian cancer cells stopped growing.

Precisely how ovarian and other types of cancer cells metabolically coax their neighbors to produce nutrients is still not fully known, but Nagrath’s latest work helps snap another important puzzle piece in place.

“We now know that targeting glutamine-producing enzymes in the tumor microenvironment slowed the growth of tumors,” he said. “This suggests to us that using a combination of therapies, rather than just one, to simultaneously target glutamine production and metabolism within cancer cells as well as in their surrounding environment may help us improve treatment.”

The work was funded by a St. Louis Ovarian Cancer Research Awareness grant.

Yang, L. Targeting stromal glutamine synthetase in tumors disrupts tumor microenvironment-regulated cancer cell growth. Cell Metabolism, 24 (2016), 685-700; dx.doi.org/10.1016/j.cmet.2016.10.011