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.
“Previous studies by our group and others have demonstrated that we might be able to target invadopodia to prevent cancer cell invasiveness,” says Dr. Sara Courtneidge, professor and director of the Tumor Microenvironment Program in Sanford-Burnham’s NCI-Designated Cancer Center and senior author of the study. “In this study, we established a cell-based screening assay to help us identify regulators of invadopodia formation.”
Dr. Courtneidge’s group has been studying invadopodia for a number of years with the goal of unraveling how they regulate tumor cell invasion. Here, her team, led by postdoctoral researcher Dr. Manuela Quintavalle, joined forces with scientists in Sanford-Burnham’s Conrad Prebys Center for Chemical Genomics (Prebys Center). This collaboration provided the Courtneidge lab with extra expertise in chemical genomics, the robotic technology necessary to rapidly and reproducibly screen more than 1,000 compounds with known pharmacological activity in cell-based assays, and automated microscopy capable of detecting and measuring invadopodia formation.
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.
Taking the study a step further, Drs. Courtneidge and Quintavalle and the team also worked out exactly how Cdk5 promotes 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.
On one hand, this screening study provides the proof-of-concept that the identification of invadopodia regulators might also lead to new strategies for controlling metastatic cancer growth. But it also revealed another surprise—one that might have implications for patients treated with the cancer drug paclitaxel.
Quintavalle, M., Elia, L., Price, J., Heynen-Genel, S., & Courtneidge, S. (2011). A Cell-Based High-Content Screening Assay Reveals Activators and Inhibitors of Cancer Cell Invasion Science Signaling, 4 (183) DOI: 10.1126/scisignal.2002032