Robert Benezra: Overview
Molecular Mechanisms of Differentiation and Metastasis
Tumor metastasis, or the spread of cancer cells to distant organs, is the leading cause of death among cancer patients. The process of metastasis involves a number of critical steps including invasion of the tumor cells into a blood vessel, survival and travel in the bloodstream, exiting the blood vessel at a distant site, and then regrowth once the cells arrive at the new organ site. Each step of this process is controlled by sets of proteins that are now beginning to be identified. My laboratory focuses on the expression of a family of proteins called Id proteins, which are essential for the last step of metastasis — namely the reinitiation of tumor growth once the cancer cell has taken up residence at a new site. Inhibiting the activity of these proteins has been shown in animal models to severely inhibit the dissemination of cancer cells and presents a novel therapeutic approach to the management of metastasis in patients.
The Id proteins were first identified as proteins that controlled the growth and specialization of cells in the early embryo. It was shown that high levels of Id expression were required for cells in the embryo to undergo the appropriate number of rounds of cell division before they began to develop into specialized cells of certain tissues (such as muscle and brain and blood vessels), at which time they stop dividing and perform the necessary function of those particular tissue types. Remarkably, when the Id proteins are re-expressed in cancer cells, they do a very similar thing — they allow the tumor cells to continue to divide, particularly when they arrive at distant organ sites during metastasis. In collaboration with Sloan Kettering Institute Director Joan Massague’s laboratory at SKI, we have shown that when Id proteins are depleted, breast tumor cells fail to reinitiate growth when they arrive in the lung, a major metastatic site in breast cancer progression.
The growth of blood vessels at metastatic sites is also under the control of Id proteins. When metastatic tumors begin to grow, they recruit rapidly growing blood vessels that re-express the Id proteins. Importantly, Id proteins are not expressed in normal “resting” blood vessels, making them attractive therapeutic targets. Our lab has shown over the past decade that the re-expression of the Id proteins is essential for the formation of a functioning blood-vessel network at sites of metastasis. The Id-expressing, blood-vessel-forming cells are recruited from the bone marrow to the site of metastasis. Inhibiting these proteins in the bone marrow in mouse models decreases the integrity of the vasculature at metastatic sites and thereby starves the growing cancer cells of necessary oxygen and nutrients.
In an effort to apply these findings to the development of a new class of drugs, we have devised a strategy to inhibit the activity of Id proteins in living animals. By delivering a molecule capable of inhibiting the production of Id proteins specifically to tumor blood vessels, we have shown we can successfully reduce Id protein levels in these vessels with minimal side effects and a concomitant inhibition of metastatic progression in a mouse model of breast cancer. Our hope is that these findings will facilitate the clinical development of a new class of well-tolerated, anti-metastatic drugs that will ultimately benefit our patients.
Molecular Mechanisms of Maintenance of Chromosome Stability
Dividing cells must ensure that each of the two daughter cells receives an exact duplicate of all chromosomes to ensure fitness. The acquisition of aneuploidy, or abnormal chromosome numbers, has long been associated with tumor relapse, metastasis, and poor prognosis in a wide variety of human cancers. Recently it has been shown in a large number of mouse modeling studies, including those from our lab, that aneuploidy is not simply a passenger but rather can drive the generation of more aggressive disease and fuel recurrence after tumor regressions. In addition to the gains in tumor-promoting oncogenes or loss of tumor suppressors that result from numerical chromosome changes, it is now becoming clear that chromosome missegregation events can lead directly to DNA damage and changes in metabolism that can further fuel the rapid growth and fitness of tumor cells.
Our lab has shown that a major driver of aneuploidy in human cancers is the overexpression of genes involved in monitoring proper chromosome segregation. This process, referred to as the spindle assembly checkpoint (SAC), is designed to sense if any individual chromosome is unattached to the spindle apparatus, which pulls each chromosome copy to the two daughter cells. The proteins that execute the SAC are, somewhat surprisingly, often overexpressed in cancer because their expression is repressed by gene products (namely p53 and Rb) that are often lost in cancer. Overexpression of components of the SAC lead to a failure of chromosomes to segregate properly as a result of a failure to degrade the proteins (cohesins) which encircle the two copies of each replicated chromosome. The timing of cohesin loss is important to allow each chromosome to find its way to the proper daughter cell.
By exploring the molecular mechanisms that control the proper expression of genes involved in the SAC and understanding how the SAC itself is extinguished once all chromosomes are properly attached to the spindle, we hope to uncover new vulnerabilities in the aggressive and often drug-resistant cancer cells that have acquired abnormal chromosome numbers.