Mitotic defects in tumor promotion, suppression, and response to chemotherapy

Beth Weaver

 

Dr. Beth Weaver

March 1 at 12:20pm in the Fralin Auditorium, Fralin Hall room 102

Hosted by Dr. D. Cimini

 

Dr. Weaver received a Bachelor of Science degree in Biochemistry from Brown University in Providence, RI and a PhD in Biomedical Sciences from the University of California, San Diego, where she studied mitosis and the mitotic checkpoint. During her postdoctoral training at the Ludwig Institute for Cancer Research in La Jolla, CA, she tested the impact of aneuploidy on tumor initiation. In 2008, she joined the faculty at the University of Wisconsin-Madison. She is currently an Associate Professor in the Departments of Cell and Regenerative Biology and Oncology/McArdle Laboratory for Cancer Research.  Research interests in the Weaver laboratory focus on the consequences of chromosome segregation errors during mitosis on tumor initiation, progression, and response to chemotherapy, as well as identifying interphase functions of mitotic proteins that influence their effect on tumors. Additional research interests include the interplay between mitotic errors and radiation therapy in HPV positive tumors. The overall goal of her research program is to leverage fundamental insights into mitosis to improve anti-cancer therapies that impact mitosis.

Aneuploidy, an abnormal chromosome number, is hallmark of human tumors proposed to promote tumor initiation and/or progression. However, aneuploidy can both promote and suppress tumors, depending on the rate of chromosome missegregation/chromosomal instability (CIN); low CIN is weakly tumor promoting, while high CIN causes cell death and tumor suppression. We have shown that the microtubule poison paclitaxel (TaxolTM), the best selling chemotherapy drug in history, does not accumulate in primary breast cancers at sufficient concentrations to cause mitotic arrest. Instead, our results suggest that paclitaxel and other microtubule poisons in clinical use increase the rate of CIN over a maximally tolerated threshold in tumors with a pre-existing rate of low CIN. Causes of the widespread low CIN in human cancer remain unclear. Upregulation of the mitotic checkpoint gene Mad1 causes low CIN, and also results in reduced protein levels of the p53 tumor suppressor by preventing sequestration of MDM2, the E3 ubiquitin ligase that targets p53 for degradation.  Upregulation of the mitotic kinase Aurora B also causes low CIN and, remarkably, reduces phosphorylation of Aurora B substrates. Expanding our understanding of mitosis, aneuploidy, and CIN in cancer is likely to result in improved anti-cancer treatment strategies and patient outcomes.

Zasadil et al, Cytotoxicity of paclitaxel in breast cancer is due to chromosome missegregation on multipolar spindles. Sci Transl Med 2014. PMID: 24670687.

Wan et al, A Golgi-localized pool of the mitotic checkpoint component Mad1 controls integrin secretion and cell migration. Curr Biol 2014. PMID: 25447996.

Zasadil et al, High rates of chromosome missegregation suppress tumor progression but do not inhibit tumor initiation. Mol Biol Cell 2016. PMID: 27146113.

Funk et al, Living in CIN: Mitotic Infidelity and Its Consequences for Tumor Promotion and Suppression. Dev Cell 2016. PMID: 27997823.

Flyer

This seminar will NOT be livestreamed or recorded.