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.
