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Aneuploidy and disease: Cancer and Down Syndrome

How does aneuploidy promote tumorigenesis?

Our studies show that aneuploidy has highly detrimental effects on the fitness of primary cells. More recently we found that this is also true in the context of oncogenic transformation (Figure 1).

An aneuploid karyotype antagonizes proliferation, anchorage independent growth and proliferation in xenografts of immortalized and transformed cells. These findings raise an interesting conundrum. How is it possible that aneuploidy invariably inhibits proliferation yet is associated with aggressive disease in the clinic?

We are testing two non-mutually exclusive possibilities to explain this apparent discrepancy. Experimental evolution studies in microorganisms have shown that aneuploidy can endow cells with new traits. We are testing the possibility that aneuploidy confers metastatic potential and chemotherapy resistance to tumor cells using multiple mouse models of aneuploidy that we and others have developed. The second possibility that we are testing is that aneuploidy functions as a mutator that is, owing to its genome-instability inducing properties, accelerates cancer cell evolution (Figure 2).

Given the significant fitness penalty associated with aneuploidy, genetic alterations that confer aneuploidy tolerance could promote the evolution of aggressive disease. We have begun to identify second site suppressors of the proliferation defect of aneuploid yeast cells. Their molecular characterization revealed strain-specific genetic alterations as well as mutations shared between different aneuploid strains. Among the latter, a loss of function mutation in the gene encoding the deubiquitinating enzyme UBP6 improves growth rates of most aneuploid yeast strains under conditions of elevated proteotoxicity (high temperature; Figure 3).

The deletion does so by attenuating the changes in intracellular protein composition caused by aneuploidy. Our results demonstrate the existence of aneuploidy-tolerating mutations and highlight the importance of ubiquitin-proteasomal degradation in suppressing the adverse effects of aneuploidy. We are now in the process of characterizing additional aneuploidy-tolerating mutations in detail in the hope that they will shed light on how cancer cells escape the adverse effects of aneuploidy and allow them to take advantage of potential pro-tumorigenic traits that the condition confers.

Aneuploidy – a therapeutic target in cancer?

Single sequencing shows that normal human tissues are euploid. Compounds that specifically target the aneuploid state would therefore represent cancer therapeutics with ideal characteristics - broad efficacy yet high selectivity. The discovery that aneuploidy causes a decrease in cellular fitness, prompted us to search for genetic and chemical perturbations that exhibit synthetic lethality with the aneuploid state either by exaggerating the adverse effects of aneuploidy and/or interfering with pathways essential for the survival of aneuploid cells. Genetic screens in yeast and chemical genetic approaches in mammalian cell lines showed that such synthetic lethal interactions indeed exist. Our results further suggest that compounds that interfere with pathways essential for the survival of aneuploid cells could serve as a new treatment strategy against a broad spectrum of human tumors, especially when combined with traditional chromosome mis-segregation inducing chemotherapeutics (i.e. taxanes). We continue to conduct genetic and chemical screens in yeast and human cells. It is our hope that understanding the effects of the identified compounds on aneuploid cells will pave the way for the development of new cancer treatments.

The biology of Down Syndrome.

Down Syndrome (DS) is caused by trisomy for chromosome 21. The condition has a severe impact on health. 87.5 percent of DS fetuses die in utero. Individuals born with the condition suffer from mental retardation, facial dysmorphology, hypotonia, and dermatoglyphic features. Predisposition for certain diseases is also increased. Identifying the source of the phenotypes observed when chromosome 21 is triplicated, is central to understanding Down Syndrome. Changes in copy number, and so expression level, of a relatively small subset of genes – known as dosage sensitive genes (DSGs) –could be responsible for the DS phenotypes. Alternatively, aneuploid phenotypes may be the consequence of copy number changes of numerous genes, which when mis-expressed on their own have little phenotypic impact. The “few critical genes” hypothesis predicts that a small number of triplicated genes cause the growth, developmental and cognitive abnormalities characteristic of the condition. Indeed, previous studies mapped DS phenotypes to a genomic region known as the “Down Syndrome critical region” (DSCR). While some characteristics of DS can be attributed to changes in dosage of specific genes, other characteristics such as decreased proliferative capacity of trisomy 21 cells may be caused by cumulative effects of genes for which individual copy number alteration has a minimal effect on fitness.

To investigate which aspect of the aneuploid condition – individual DSGs or cumulative effects of many genes – are responsible for specific phenotypes we study yeast strains with defined aneuploidies and Trisomy 21 cell lines. We also aim to identify genes responsible for the various Down Syndrome phenotypes and understand phenotypic variability that is so characteristic of the condition.

Recent Publications:

Bonney ME, Moriya H, Amon A. Aneuploid proliferation defects in yeast are not driven by copy number changes of a few dosage-sensitive genes. Genes Dev. 2015 May 1; 29(9): 898-903. PMCID: PMC4421978

Dodgson SE, Kim S, Costanzo M, Baryshnikova A, Morse DL, Kaiser CA, Boone C, Amon A. Chromosome-Specific and Global Effects of Aneuploidy in Saccharomyces cerevisiae. Genetics. 2016 Apr;202(4):1395-1409. doi: 10.1534/genetics.115.185660. Epub 2016 Feb 2.

Sheltzer JM, Ko JH, Replogle JM, Habibe Burgos NC, Chung ES, Meehl CM, Sayles NM, Passerini V, Storchova Z, Amon A. Single-chromosome aneuploidy commonly functions as a tumor suppressor. Cancer Cell in press.

Tang YC, Williams BR, Siegel JJ, Amon A. Identification of aneuploidy-selective antiproliferation compounds. Cell. 2011 Feb 18; 144(4): 499-512. NIHMSID #: 276601

Torres EM, Dephoure N, Panneerselvam A, Tucker CM, Whittaker CA, Gygi SP, Dunham MJ, Amon A. Identification of Aneuploidy-Tolerating Mutations. Cell. 2010 Oct 1; 143(1): 71-83. Epub 2010 Sep 16. PMCID: PMC2993244