Cancer onset and progression can be affected by diet, but knowing which nutrients are most important and how they affect cancer cells is less completely understood. Now a cancer biologist at The University of Texas Southwestern Medical Center is examining the differences in metabolism between cancer cells and normal ones in order to figure out how to starve cancer cells of the nutritional resources they need in order to survive.
Michalis Agathocleous was a postdoctoral researcher at UT Southwestern, and a First-Time Tenure-Track Award from CPRIT in 2017 enabled him to stay on as a faculty member to continue his research at the Children’s Research Institute.
Agathocleous found a new way to study the metabolism of small populations of cells. This allows him to investigate the metabolism of stem cells, which are rare compared to normal, differentiated cells. Stem cells can live for the entire lifetime of an organism to repopulate normal cells when they become depleted, and can become cancerous if they are mutated.
Agathocleous is specifically studying stem cells in bone marrow, which when mutated can cause leukemias to develop. His research was the first to show that there are physiological differences in the levels of nutrients essential for metabolism between stem cells and other cells. For example, stem cells accumulate Vitamin C at much greater levels than normal cells, which appears to have a protective effect against even mutated cells becoming cancerous.
In mice, Vitamin C helps an enzyme, called TET2, that protects against cancer. This same enzyme is mutated in many human leukemias.
From population studies, scientists know that people who have measurably lower levels of Vitamin C in their blood, later tend to die from cancer at higher rates than people who have normal levels of the vitamin. Whether low Vitamin C has a causal relationship with cancer mortality is an open question, but Agathocleous’s research seems to suggest it might. So far, he’s only studied mice, so it’s not known if the same applies to humans.
Now he is continuing his studies of Vitamin C by asking whether or not temporary depletion of Vitamin C inside a cell has an effect on the cell’s future function.
Vitamin C affects so-called “epigenetic marks,” which include chemical groups added to or deleted from DNA that can regulate which genes are expressed. These can be carried over from one generation of a cell to the next when the cell divides. If Vitamin C is depleted, this raises the possibility that its reduction might leave a permanent mark on stem cells.
“We can test the idea whether these epigenetic marks can actually be the substrate for a kind of memory, or not,” he says. “It’s possible that when the environment changes, stem cells change, but when the environment returns to normal, stem cells return to normal, too, and there is no memory. The other possibility is that even after Vitamin C returns to normal levels, the epigenome keeps a memory of the depletion that came before, and that might affect whether the stem cell becomes cancerous.”
“I’m very grateful to CPRIT and the people of Texas, because we wouldn’t be able to do what we do without them,” he says. “And it’s a marvelous thing for the people of a state to decide to fund cancer research.”
Agathocleous was both an undergraduate and a graduate student at the University of Cambridge, in England, and then remained there as a research fellow after receiving his Ph.D. in development and neuroscience in 2007. He came to the Children’s Research Institute at UT Southwestern as an assistant instructor and research fellow in 2011.