Grantee: Nada Kalaany, PhD
Institution: Boston Children’s Hospital
Area of Focus: Tumor Biology and Genomics
Grant Term: 7/1/2017-6/30/2021
"The results of our study are exciting because they reveal how cancer cells manage to aggressively grow within a seemingly hostile, nutrient-deprived environment—a puzzling characteristic of pancreatic tumors. We identified glutamine synthetase as a key player and a potentially targetable dependency in the nutrient-deprived—and likely most aggressive—cancer-cell clusters within the pancreatic tumor. It’s possible that this target is also relevant to cancers of other tissues.
“It was most exciting to us to find out that the adaptation of pancreatic cancer cells to nutrient-deprivation is reversible, highlighting their nongenetic metabolic flexibility. We also revealed a weakness and potential target for a new drug that doctors may be able to use with patients in the future."
The Challenge: Like all cells in the body, cancer cells need nutrients to grow. One of the most important nutrients is glutamine, an amino acid used to build proteins. Glutamine is the second most abundant nutrient in the blood, after glucose (a type of sugar).
Without glutamine, cancer cells would stop growing and eventually die. Because of this, for years, many scientists have considered glutamine as cancer’s Achilles' heel and have been looking for a way to cut off cancer cells’ access to it.
But even when glutamine levels appear to be low, some cancer cells continue to grow. How? Scientists are learning that cancer cells adapt, or reprogram, their metabolism to supplement their glutamine supply.
The Research: Pancreatic cancer is a type of cancer that thrives in a harsh, nutrient-deprived setting. Its cells grow encapsulated in a dense, mesh-like network made of secreted proteins and other non-cancer cells, restricting blood flow, and hence, the cancer’s access to nutrients. Yet, somehow, cancer cells are still able to grow and spread.
Earlier studies showed that when pancreatic cancer cells were deprived of either glucose or glutamine, the cells become more dependent on the non-depleted nutrient—managing to still generate the energy and building blocks they needed to grow.
“Our study is novel,” said American Cancer Society (ACS) grantee, Nada Kalaany, PhD, “because we aimed to deprive pancreatic cancer cells of both of their preferred nutrients.” This created a condition that more closely mimicked the environment of pancreatic cancer cells in the body, she explained. “Doing that helped us identify how cells were able to aggressively grow, despite starvation.”
Kalaany and her research team reported their findings about how pancreatic cancer cells do this in a recently published study in Cell Biology.
They found that without glucose and glutamine, the vast majority of pancreatic cancer cells died. However, those that survived, adapted. As they were adapting, they became able to “turn on” the production of glutamine synthetase and prevent it from being broken down. (Glutamine synthetase is the enzyme involved with the production of glutamine in nutrient-deprived cancer cells.)
“Interestingly, we learned that this higher level of fitness or aggressiveness of the cancer cells is not the result of genetic mutations,” Kalaany said. “We knew that because the cancer cells can turn back to growing more slowly or even die, switching the production of this enzyme on and off, depending on the absence or presence of glutamine around them.”
She and her team demonstrated that the pancreatic cancer cells surviving chronic nutrient deprivation develop reversible, nongenetic changes. These changes allow them to switch between metabolic states that are best for growth when nutrients are readily available or when nutrients are sparse.
This metabolic flexibility represents a significant advantage to the tumor cells, but it also points to a new Achilles' heel for pancreatic cancer cells, a new potentially targetable weakness.
This knowledge is a new first step to learning how to slow or stop the activity of glutamine synthetase with the development of a new drug, thereby slowing or stopping the growth of these aggressive, nutrient-deprived cancer cells.
Why Does It Matter? Cells that reprogram and rewire many metabolic pathways to stay alive is one of the emerging hallmarks of cancer. Identifying how cancer cells can metabolically adapt when nutrients are scarce may help pave the way for the development of new targeted therapies to treat many types of cancers including pancreatic cancer. Such treatments could help some people with pancreatic cancer live longer.