Studying for Metastasis Cancer Body

Dr. Courtneidge’s group has been studying invadopodia for a number of years with the goal of unraveling how they regulate tumor cell invasion.
Taking the study a step further, Drs. Courtneidge and Quintavalle and the team also worked out exactly how Cdk5 promotes invadopodia formation.
Metastasis the spread of cancer from the place where it first started to another place in the body is the most common reason that cancer treatments fail.

To metastasize, some types of cancer cells rely on invadopodia, cellular membrane projections that act like feet, helping them “walk” away from the primary tumor and invade surrounding tissues.
To determine how cells control invadopodia formation, Sanford-Burnham scientists screened a collection of pharmacologically active compounds to identify those that either promote or inhibit the process. They turned up several invadopodia inhibitors that target a family of enzymes called cyclin-dependent kinases (Cdks), revealing a previously unrecognized role for Cdks in invadopodia formation. These findings appeared online July 26 in Science Signaling.

The team was surprised to find that several of the newly identified compounds that blocked invadopodia (and therefore cancer cell invasion) targeted Cdks, a family of enzymes that were not previously associated with invadopodia. In follow-up experiments, they demonstrated that one of these enzymes, Cdk5, is required for the formation and function of invadopodia and for cellular invasion, both important steps in cancer metastasis. Cdk5 is highly expressed in neurons, where it’s involved in neuronal migration and outgrowth. This is the first time the enzyme has been implicated in invadopodia formation.

Cdk5’s action leads to the degradation of another protein called caldesmon. Caldesmon was previously shown to negatively regulate invadopodia, so Cdk5 essentially removes that brake. That’s why the Cdk inhibitors identified in the screening study also inhibited invadopodia.

Heart disease is the leading cause of death

Heart disease is the leading cause of death in all over the countries. While many factors work together to contribute to heart disease including environment, lifestyle, and genetics
To address the third factor (genetics), researchers at Sanford-Burnham recently turned to fruit flies.

Fly and human genes are so closely related that the sequences of newly discovered human genes, including many that contribute to disease, can often be matched up with fly counterparts.
Since fruit flies are relatively easy to work with (they’re small, breed quickly, and don’t require a lot of maintenance), they often give scientists clues to the functions of human genes and helps them develop drugs that target them.

As Dr. Rolf Bodmer, director of Sanford-Burnham’s Development and Aging Program, explains in the Journal of Cell Biology, “We use fruit flies to learn about the fundamental genetic mechanisms that are important for the development and function of the heart.”

Dr. Bodmer himself discovered early in his career that flies lacking Tinman, a protein that regulates the expression of other genes, fail to develop heart tissue during embryonic development. If Tinman is removed later during fly development, the flies’ hearts don’t function properly.

Now researchers in Dr. Bodmer’s lab, led by postdoctoral researcher Dr. Li Qian, uncovered a genetic network that controls heart development and function in fruit flies and mice, with additional clues that it might also play a role in human heart health.

In a study published June 20 in the Journal of Cell Biology, the researchers first found a genetic link between Tinman and a protein called Cdc42 in fruit flies. Cdc42 is well known to regulate actin filaments, which act like scaffolding to help cells maintain their shape. Without fully functioning Tinman and Cdc42, the flies’ hearts didn’t beat as regularly and heart muscle fibers weren’t arranged in a parallel, organized fashion like they are in normal flies.

But Dr. Bodmer, Dr. Qian, and colleagues didn’t stop with fruit flies—they also wanted to see if Tinman and Cdc42 affect heart development and function in mice. Indeed, they found that mice with reduced Tinman and Cdc42 levels experienced poor heart contraction and rhythm. But, in a final layer of complexity, the team also discovered how Tinman works—it inhibits microRNAs, small strands of genetic material that can influence protein production. More specifically, Tinman impairs one microRNA called miR1, which in turn decreases levels of Cdc42 and another gene. In other words, miR1 serves as the middleman in the interaction between Tinman and Cdc42, and the other genes they regulate.

Finally, to determine how their lab findings might translate into human disease, Dr. Qian and colleagues screened more than 600 heart disease patients to find mutations in the gene that codes for Cdc42. They found one patient with a Cdc42 mutation that was not found in healthy control patients, suggesting that malfunctions in this pathway might impact human health.

“Our next goal is to look for more genes that interact with Tinman or with other factors that we know are important for the heart,” says Dr. Bodmer.