Metabolism & Biochemical Signaling
Building a Roadmap
Metabolic researchers don’t wear hard hats, but they are building a big-picture roadmap, an atlas of sorts, of cancer cell signaling – the highways and byways, the bypasses and feedback loops and junctions that cancer cells come to rely on.
All of this happens at a tiny scale as Thomas Graeber, PhD, investigates how the metabolism of glucose, among other nutrients, affects biochemical signaling in cancer cells. He and his colleagues use a biological systems approach to uncover the network of signals that respond when they deprive cancer glucose, its sweet fuel.
How withholding glucose kills cancer cells
Graeber, the co-leader of UCLA’s Metabolomics Center, found that withholding glucose activated a metabolic and signaling amplification loop. As a result, cancer cells die from the lethal accumulation of reactive oxygen species.
In other words, cancer cells ramped up signaling as they lost viability, which led to increased production of toxic chemicals. Because cancer cells live on the edge of what is metabolically feasible, this amplifying cycle of oxidative stress ultimately overwhelms and kills the cancer cell. As a result, researchers may be able to use agents that upset this delicate balance and induce what Graeber terms “a metabolic catastrophe.”
Advanced tools to measure cell signaling
Graeber, a professor of molecular and medical pharmacology, has built a core of resources, infrastructure and advanced tools that UCLA investigators use widely, even outside of metabolism research.
These tools, such as high-density mass spectrometry-based phosphoproteomic and metabolomic profiling, allow researchers to measure hundreds of signaling events that occur concurrently within cancer cells.
Using these measurements, scientists could build a diagram of the interconnections of “crosstalk” within cancer cells. Among other things, this work could reveal how cancer cells:
- Put metabolism into hyper drive to grow
- Selectively use nutrients
- Become resistant to drug therapy
“These patterns point us to previously unknown interactions that are crucial for cancer success. The patterns also may highlight vulnerabilities that might be targeted. We want the molecular data to guide us to what ultimately could be used to shut down cancer’s altered metabolism.” - Dr. Thomas Graeber
Understanding metabolism and cell growth
Cancer often co-opts pre-existing metabolic programs that exist within cells to perform specialized functions. For example, to grow fast, cancer could use the metabolic template immune cells use.
Even within the immune system, though, different cells play distinct roles. Each cell has its own metabolic growth profile.
Graeber’s team wants to figure out all the varied patterns of metabolic cell growth. Some of the known patterns include:
- Killer T cells use a very efficient system to get energy into the cell and build all the components needed to produce lots of T cells very quickly.
- Some cancers may use that template. Other tumors switch on other metabolic programs.
- If deprived of glucose, cancer cells may turn to burning fatty acids.
- Alternatively, cancer cells may prefer using amino acids.
In essence, Graeber’s team studies the reverse aspects of Heather Christofk, PhD’s investigations. Learn more about Christofk’s work with cancer and glucose metabolism.