Research Reveals New Insights into Brain Cancer Metabolism

Scientists have found that brain cancer cells modify their sugar metabolism, which can be targeted in mice to slow tumor growth and improve treatment results.

Glioblastomas represent the most aggressive form of brain tumor, with typical patient survival lasting just one to two years.

In these tumors, normal brain cells alter their function, dividing rapidly and invading nearby areas. Unlike healthy cells, cancerous ones use nutrients differently.

A recent study published in Nature by researchers at the University of Michigan, including specialists from the Rogel Cancer Center and other departments, examined how glioblastoma cells utilize glucose.

The research indicates these tumors depend on unique nutrient pathways, presenting potential new avenues for treatment.

“We made dietary changes in mouse models and significantly impeded tumor growth,” said co-senior author Daniel Wahl, M.D., Ph.D., an associate professor in radiation oncology.

“This research could pave the way for new therapeutic options for patients soon.”

Standard treatments include surgery followed by radiation and chemotherapy; however, tumors often recur and develop resistance.

Research has previously indicated that this resistance stems from metabolic alterations in the cancer cells.

Distinct Sugar Utilization in Cancer Cells

Metabolism refers to how our bodies process molecules like carbohydrates for energy and cellular functions.

While both brain and cancer cells utilize sugar, investigators aimed to determine if their approaches differ.

They introduced small amounts of labeled sugar into both mice and patients with brain tumors to trace its usage.

“Understanding these brain cancers to enhance patient treatments required studying the tumors in actual patients, not just in lab settings,” said co-senior author Wajd Al-Holou, M.D., a neurosurgeon leading the Michigan Multidisciplinary Brain Tumor Clinic.

Although both normal and tumor cells consumed substantial sugar, the purposes diverged considerably.

Brain Cells vs. Glioblastomas

“It’s like a metabolic fork in the road,” noted Andrew Scott, Ph.D., a researcher in Wahl’s lab.

“The brain directs sugar for energy and neurotransmitter synthesis, whereas tumors redirect it towards materials for creating more cancer cells.”

The study revealed that healthy brain tissues use sugars for energy and to produce necessary chemicals for proper function.

In contrast, glioblastomas turn off those processes, converting sugar into nucleotides—essential components of DNA and RNA—facilitating their growth and invasion.

Potential of Amino Acid-Restricted Diets

The researchers observed additional significant differences as well.

The normal brain uses sugar to form amino acids, essential for protein synthesis. However, tumor cells appeared to deactivate this pathway, instead extracting amino acids from blood.

This led the researchers to explore whether reducing specific amino acid levels could influence brain cancer while sparing healthy tissue.

They examined whether mice on an amino acid-restricted diet had improved treatment outcomes.

“Removing serine and glycine from the diet of mice resulted in a better response to radiation and chemotherapy, and the tumors were smaller compared to those fed serine,” explained co-senior author Deepak Nagrath, Ph.D., a biomedical engineering professor.

Utilizing their observations in mice, the team developed mathematical models to track glucose utilization in various pathways, potentially uncovering more drug targets.

Co-senior author Costas Lyssiotis, Ph.D., likened metabolic pathways to roads and drugs to obstacles.

“Blocking traffic on a busy highway has a more substantial effect than on a quiet back road,” he emphasized.

While healthy brains absorb amino acids like serine from the blood at a slower pace, brain cancer operates more like a busy freeway, presenting a chance to target them selectively.

The team plans to initiate clinical trials to examine whether diets that reduce blood serine levels can benefit patients with glioblastoma.

“This is a collaborative effort across the university,” said Wahl.

“No single investigator could accomplish this, and I’m grateful to be part of a team dedicated to meaningful discoveries that enhance patient treatment.”