MSGID: 1:317/3 64a79523   
   PID: hpt/lnx 1.9.0-cur 2019-01-08   
   TID: hpt/lnx 1.9.0-cur 2019-01-08   
    Eliminating extra chromosomes in cancer cells prevent tumor growth   
      
      
     Date:   
         July 6, 2023   
     Source:   
         Yale University   
     Summary:   
         Cancer cells with extra chromosomes depend on those chromosomes for   
         tumor growth, a new study reveals, and eliminating them prevents   
         the cells from forming tumors. The findings, said the researchers,   
         suggest that selectively targeting extra chromosomes may offer a   
         new route for treating cancer.   
      
      
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   Cancer cells with extra chromosomes depend on those chromosomes for   
   tumor growth, a new Yale study reveals, and eliminating them prevents   
   the cells from forming tumors. The findings, said the researchers,   
   suggest that selectively targeting extra chromosomes may offer a new   
   route for treating cancer.   
      
   The study was published July 6 in the journal Science.   
      
   Human cells typically have 23 pairs of chromosomes; extra chromosomes   
   are an anomaly known as aneuploidy.   
      
   "If you look at normal skin or normal lung tissue, for example, 99.9%   
   of the cells will have the right number of chromosomes," said Jason   
   Sheltzer, assistant professor of surgery at Yale School of Medicine and   
   senior author of the study. "But we've known for over 100 years that   
   nearly all cancers are aneuploid."  However, it was unclear what role   
   extra chromosomes played in cancer -- for instance, whether they cause   
   cancer or are caused by it.   
      
   "For a long time, we could observe aneuploidy but not manipulate it. We   
   just didn't have the right tools," said Sheltzer, who is also a researcher   
   at Yale Cancer Center. "But in this study, we used the gene-engineering   
   technique CRISPR to develop a new approach to eliminate entire chromosomes   
   from cancer cells, which is an important technical advance. Being able   
   to manipulate aneuploid chromosomes in this way will lead to a greater   
   understanding of how they function."  The study was co-led by former   
   lab members Vishruth Girish, now an M.D.-Ph.D.   
      
   student at Johns Hopkins School of Medicine, and Asad Lakhani, now a   
   postdoctoral researcher at Cold Spring Harbor Laboratory.   
      
   Using their newly developed approach -- which they dubbed Restoring   
   Disomy in Aneuploid cells using CRISPR Targeting, or ReDACT -- the   
   researchers targeted aneuploidy in melanoma, gastric cancer, and ovarian   
   cell lines. Specifically, they removed an aberrant third copy of the   
   long portion -- also known as the "q arm" -- of chromosome 1, which   
   is found in several types of cancer, is linked to disease progression,   
   and occurs early in cancer development.   
      
   "When we eliminated aneuploidy from the genomes of these cancer cells,   
   it compromised the malignant potential of those cells and they lost   
   their ability to form tumors," said Sheltzer.   
      
   Based on this finding, the researchers proposed cancer cells may have   
   an "aneuploidy addiction" -- a name referencing earlier research that   
   discovered that eliminating oncogenes, which can turn a cell into a cancer   
   cell, disrupts cancers' tumor-forming abilities. This finding led to a   
   model of cancer growth called "oncogene addiction."  When investigating   
   how an extra copy of chromosome 1q might promote cancer, the researchers   
   found that multiple genes stimulated cancer cell growth when they were   
   overrepresented -- because they were encoded on three chromosomes instead   
   of the typical two.   
      
   This overexpression of certain genes also pointed the researchers to a   
   vulnerability that might be exploited to target cancers with aneuploidy.   
      
   Previous research has shown that a gene encoded on chromosome 1, known as   
   UCK2, is required to activate certain drugs. In the new study, Sheltzer   
   and his colleagues found that cells with an extra copy of chromosome 1   
   were more sensitive to those drugs than were cells with just two copies,   
   because of the overexpression of UCK2.   
      
   Further, they observed that this sensitivity meant that the drugs could   
   redirect cellular evolution away from aneuploidy, allowing for a cell   
   population with normal chromosome numbers and, therefore, less potential   
   to become cancerous. When researchers created a mixture with 20% aneuploid   
   cells and 80% normal cells, aneuploid cells took over: after nine days,   
   they made up 75% of the mixture. But when the researchers exposed the   
   20% aneuploid mixture to one of the UCK2-dependent drugs, the aneuploid   
   cells comprised just 4% of the mix nine days later.   
      
   "This told us that aneuploidy can potentially function as a therapeutic   
   target for cancer," said Sheltzer. "Almost all cancers are aneuploid,   
   so if you have some way of selectively targeting those aneuploid cells,   
   that could, theoretically, be a good way to target cancer while having   
   minimal effect on normal, non-cancerous tissue."  More research needs   
   to be done before this approach can be tested in a clinical trial. But   
   Sheltzer aims to move this work into animal models, evaluate additional   
   drugs and other aneuploidies, and team up with pharmaceutical companies   
   to advance toward clinical trials.   
      
   "We're very interested in clinical translation," said Sheltzer. "So we're   
   thinking about how to expand our discoveries in a therapeutic direction."   
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   Worthy_of_a_Toast Story Source: Materials provided by   
   Yale_University. Original written by Mallory Locklear.   
      
   Note: Content may be edited for style and length.   
      
      
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   Journal Reference:   
      1. Vishruth Girish et al. Oncogene-like addiction to aneuploidy   
      in human   
         cancers. Science, 2023 DOI: 10.1126/science.adg452   
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   Link to news story:   
   https://www.sciencedaily.com/releases/2023/07/230706152349.htm   
      
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