Abstract: Series 110, Lecture 4

The Harvey Lectures Series 110 (2014—2015)

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Lecture #4: Thursday, February 19, 2015 — Watch Video of Lecture

Consequences of Aneuploidy

Angelika Amon, PhD

Angelika Amon, PhD

Professor, David H Koch Institute for Integrative Cancer Research
Investigator, Howard Hughes Medical Institute

Howard Hughes Medical Institute, Massachusetts Institute of Technology

Cambridge, Massachusetts

Dr Amon's Website

Aneuploidy, a karyotype that is not a multiple of the haploid complement, is a hallmark of cancer. 90 percent of all solid human tumors harbor an incorrect karyotype. Thus, determining how aneuploidy arises and how it impacts cellular behavior is critical for our understanding of tumorigenesis. We developed yeast and mouse models to study the effects of aneuploidy on cell physiology. Our analyses revealed that the condition causes chromosome-specific phenotypes, and, remarkably, phenotypes shared by many different aneuploid yeast and mouse cells, which we collectively call the aneuploidy-associated stresses. Among them, proteotoxic stress, caused by aneuploidy-induced proteomic imbalances makes aneuploid cells especially vulnerable. In aneuploid yeast, the proteasome and chaperone systems are limiting; in aneuploid mammalian cells, autophagy appears to be a rate limiting protein quality control system. The discovery of aneuploidy-associated stresses prompted us to search for compounds that selectively kill aneuploid cells. In a proof-of principle chemical screen we showed that such compounds indeed exist and, importantly, exhibit efficacy in mouse models of cancer. Despite the adverse effects of aneuploidy on cell physiology, tumor cells are highly aneuploid. We discovered that aneuploidy causes multiple forms of genome instability. This property of aneuploidy could explain why cancer cells are aneuploid. The condition could facilitate the development of genetic alterations that drive malignant growth especially in the context of mutations that suppress the adverse effects of aneuploidy. Evolution studies in yeast indicate that such mutations indeed exist. Our studies on aneuploidy shed light on tumor evolution and could pave the way for the development of new cancer therapeutics.