BA Biology, University of Rochester PhD Cell and Developmental Biology, University of California, Davis Postdoctoral Researcher, Albert Einstein College of Medicine Postdoctoral Researcher, University of North Carolina, Chapel Hill
I. Regulation of Centriole Duplication. Errors in chromosome segregation during cell division can result in the production of aneuploid daughter cells. This is particularly devastating during development, as aneuploidy is an underlying cause of miscarriage, birth defects, and cancers. During cell division, the accurate transmission of replicated chromosomes depends on the assembly of a bipolar spindle which is facilitated by the presence of centrioles, tiny organelles that help generate and organize spindle microtubules. Normally cells contain a single centriole pair, each duplicating only once prior to entering cell division. However, these mother centrioles have the capacity to assemble multiple daughters simultaneously. If cells assemble excess daughter centrioles (known as centriole amplification), then multipolar spindle assembly can ensue, leading to chromosomal instability (CIN) and increased risk for miscarriage/birth defects and cancer. How cells control centriole copy number is unclear. My lab uses the fruit fly Drosophila melanogaster as a model system to study the mechanisms that underlie centrioles duplication and function.
II. Centrosome instability in prostate cancer (PCa). We study centrosome aberrations as a major causal factor in promoting CIN in PCa. Unlike many cancers, PCa does not harbor signature mutations in key oncogenes and tumor-suppressor genes. Instead, primary prostate tumors display wide-spread CIN which may be a 'driver' of tumorigenesis in this organ. Our study of centrosomes in PCa (Wang et al., Oncogene, 2020) (1) is the first to provide a mechanism for the cause of CIN in early prostate tumors. (2) Centrosomes are frequently overduplicated (amplified) in many types of cancer, promoting both CIN and tumorigenesis. However, the opposite condition, centrosome loss has never been reported in any cancer. This is surprising because mitotic spindles are still able to form in the absence of centrosomes and these are error prone, producing identical types of CIN. Thus, one would expect that centrosome loss would be observed in cancer. Ours is the first study to show centrosome loss in any human cancer. (3) We discovered that centrosome loss is sufficient to transform cells and promote invasive tumor formation in a mouse xenograft model, producing tumors that have classic features of malignant and high grade primary human prostate carcinoma - the first demonstration that centrosome loss has oncogenic potential. Interestingly, in contrast to primary tumors, aggressive metastatic-derived PCa cells display centrosome amplification. Thus, like chromosomes, centrosomes appear to display instability as their numbers fluctuate during cancer progression. Notably, molecular alterations that promote centrosome loss or amplification are unknown. Our goals are to: (1) Determine the molecular mechanisms that underlie centrosome loss and amplification during PCa progression. (2) Test whether centrosome loss is an early 'driver' event and, through further CIN, cells transition to genotypes that trigger centrosome amplification, leading to malignant transformation. (3) Since CIN is observed in many cancers, we are interested in determining whether centrosome instability is a ubiquitous oncogenic feature of lesions, whether precancerous, benign, or metastatic.