Basic Briefs
Trafficking Control in Brain Cells
By Karuna Meda | Illustrations by Bratislav Milenkovic
A single brain cell or neuron can send signals to hundreds of others using its axon — a thin fiber that acts like a telephone cable carrying electrical messages and splitting into numerous tree-like branches. Different cellular materials need to be transported along the axon and its elaborate branches to support the development and function of brain cells, but how they do it has been a puzzle.
Neuroscientist Le Ma, PhD, and colleagues developed a simple method to tackle the question. They cultured neurons in a dish and studied transport at the junction of two branches by tagging a cellular cargo called lysosomes, small sacs that travel along branches to remove waste and recycle nutrients. They found that if the two branches were the same length, the lysosomes traveled equally to both. However, if one branch was longer than the other, more lysosomes travelled to the longer one, suggesting that branch length influenced transport.
They also looked at the growth cone — the branch tip that acts like a sensor, looking for things to grow toward or to avoid. They found that lysosomes preferred traveling to branches with more dynamic growth cones over the still ones. Interestingly, when they used a molecular tool to make a still branch more dynamic, the lysosomes swarmed to it.
“These experiments showed us how trafficking is regulated in brain cells and could give insight into how neuronal transport impacts conditions like nerve injury and memory loss,” says Dr. Ma.
Finding a Hidden Cancer Target
By Merrill Meadow + Lauren Langbein | Illustrations by Bratislav Milenkovic
Triple-negative breast cancer often fails to respond to treatments. But Jefferson researchers have identified a vulnerability in these cells, and designed a way to exploit it.
Their studies revolve around two genes: p53 and MDM2. When p53 functions properly, it can prevent cancer; and in healthy cells MDM2 turns off p53. One strategy for treating breast cancer has been to use drugs that block the MDM2 and reactivate p53.
However, most people with triple-negative breast cancer have a mutated and inactive p53 gene that allows cancers to grow. “For these patients, MDM2 inhibitors are ineffective and have toxic side effects,” explains Clare Adams, PhD, lead author on the study. That fact led scientists to assume that MDM2 drugs would not work in any cancer with a mutated or deleted p53.
“However, we discovered that deleting the MDM2 gene actually kills mouse cancer cells lacking p53,” Dr. Adams says. So, the investigators designed and tested a compound called MDM2 PROTAC that causes the MDM2 protein to be “chewed up” and eliminated from cells. “Existing MDM2 inhibitors cause a toxic build-up of MDM2, but eliminating MDM2 avoids this toxicity,” says Dr. Adams. The result: the cancer cells died, regardless of whether p53 was mutated or not, with no signs of toxicity.
“This approach could open a new chapter for many kinds of p53-mutant cancers,” says senior author Christine Eischen, PhD, the Herbert A. Rosenthal, MD ‘56 Professor of Cancer Research at the Sidney Kimmel Comprehensive Cancer Center.