P. Todd Stukenberg, Ph.D.

Research

Defects in chromosome segregation can generate aneuploidy, a condition that is found in almost all human tumors and is a major cause of miscarriages and birth defects. The complex process of chromosome segregation must be highly coordinated to ensure fidelity and prevent aneuploidy. Kinetochores are central players in mitosis. Kinetochores are complex protein machines that assemble on each chromatid. They link chromosomes to microtubules and are the motors that move chromosomes on the mitotic spindle. Kinetochores also ensure that all chromatids are attached before they are segregated, by generating signals that prevent the cell cycle machinery from entering anaphase, a process referred to as the spindle checkpoint.

In the Stukenberg lab we study how kinetochores function and how they are regulated. Surprisingly, we found that the Ndc80 complex both binds microtubules for the spindle and is required to generate spindle checkpoint signals. We are intensively studying this fascinating group of four proteins. These studies are determining how the kinetochore uses the energy stored within a microtubule to perform the work of moving chromosomes. In addition, we are determining how kinetochores generate the spindle checkpoint signal and turn it off after microtubules attach.

We also study the chromosome passenger complex, which has the Aurora B kinase as its catalytic component. Aurora B regulates kinetochores and plays an important role in the spindle checkpoint. We are dissecting how Aurora B itself is regulated and identifying the important substrates that are regulated by Aurora B. Our studies are uncovering how Aurora B can coordinate numerous mitotic processes and have recently uncovered novel functions connecting R-loops to the cohesin complex. Since Aurora kinase inhibitors are currently undergoing clinical trials as chemotherapeutics, these studies are directing clinicians to more effectively use this new class of drugs.

As an Innovation Fund investigator, P. Todd Stukenberg, Ph.D., is teaming up with Hui Zong, Ph.D., to develop a new mouse model that better represents the way human cancers develop. Tumor progression in current mouse models tends to be driven by mutations in specific genes. However, larger-scale genomic changes known as aneuploidy are poorly incorporated in existing models, even though aneuploidy has important roles in tumor development, metastasis, and immune evasion. The Stukenberg lab found that human breast tumors with a high degree of aneuploidy overexpress key transcriptional regulators of the cell cycle, which they hypothesize drives aneuploidy in these tumors. Combining expertise from Stukenberg’s work in chromosomal biology and Zong’s development of cutting-edge cancer models, the pair will engineer a novel mouse model of triple negative breast cancer that incorporates both specific gene mutations and aneuploidy. They will track the evolution of cancer in these animals from initiation to malignancy and will answer questions including how aneuploidy contributes to tumor progression and how it influences immune responses to cancer. Work from the pair will inspire a deeper understanding of tumor biology and better models to test how well drugs work against the disease.