In:
Science, American Association for the Advancement of Science (AAAS), Vol. 381, No. 6660 ( 2023-08-25)
Abstract:
It has been known for more than 100 years that human cancers exhibit pervasive aneuploidy, or chromosome copy number changes. For instance, about 25% of cancers exhibit gains of the q arm of chromosome 1. However, despite the prevalence of aneuploidy across cancer types, its role in tumorigenesis has remained poorly defined. Our ability to uncover the function of these large-scale copy number alterations has been hampered by our inability to experimentally manipulate chromosome dosage in cancer. Nonetheless, as aneuploidy is common across malignancies but rare in normal tissue, drugs that exhibit selective toxicity toward aneuploid cells could be useful anticancer agents. RATIONALE Although aneuploidies have resisted close analysis, previous research has led to the discovery of a phenomenon called “oncogene addiction.” An oncogene-addicted cancer is dependent on the expression of an individual oncogene for continued malignant growth, and loss or inhibition of that oncogene is sufficient to induce cancer regression. As specific aneuploidies such as the gain of chromosome 1q are frequent events in diverse cancer types, we hypothesized that certain aneuploidies could themselves represent oncogene-like cancer addictions. To test this hypothesis, we developed ReDACT (Restoring Disomy in Aneuploid cells using CRISPR Targeting), a set of chromosome engineering tools that allow us to eliminate individual aneuploid chromosomes from cancer genomes. Using ReDACT, we created and then characterized a panel of isogenic cells that have or lack common cancer aneuploidies. RESULTS We found that eliminating the trisomy of chromosome 1q from cancer cell lines harboring this alteration almost completely abolished anchorage-independent growth and xenograft formation. Similarly, eliminating the 1q trisomy from a nonmalignant cell line blocked RAS -mediated transformation. Prolonged growth in vitro or in vivo after aneuploidy elimination in cancer cell lines led to karyotype evolution, and 1q-disomic cells were eventually outcompeted by cells that had recovered the 1q trisomy. In contrast, removing other trisomic chromosomes from cancer cells had variable effects on malignant growth, demonstrating that different aneuploidies have distinct phenotypic consequences for cancer development. An analysis of clinical sequencing data demonstrated that chromosome 1q gains arise early during tumorigenesis and are mutually exclusive with mutations in the tumor suppressor TP53 , suggesting that 1q trisomies could represent a mutation-independent mechanism for blocking p53 signaling. Consistent with this, we demonstrated that ReDACT-mediated elimination of chromosome 1q trisomies increased the expression of p53 target genes in TP53 wild-type cell lines. We traced this suppression of p53 function to the triplication of MDM4 , a p53 inhibitor encoded on chromosome 1q, and we found that deleting a single copy of MDM4 impaired the growth of 1q-trisomic cells, whereas moderate overexpression of MDM4 rescued the growth of 1q-disomic cells. Finally, we demonstrated that chromosome 1q gains result in the overexpression of UCK2 , a nucleotide kinase encoded on chromosome 1q that is also required for the cytotoxicity of certain anticancer nucleotide analogs. We determined that several different 1q-trisomic cell lines displayed enhanced sensitivity to these compounds owing to the up-regulation of UCK2 , revealing that 1q aneuploidy can also represent a tractable cancer vulnerability. CONCLUSION Certain aneuploidies that are commonly found in tumor genomes play a central role in cancer development, and eliminating these aneuploidies compromises malignant growth potential. At the same time, aneuploidy causes collateral therapeutic vulnerabilities that can be targeted to selectively eliminate cells with chromosome dosage imbalances. The development of flexible chromosome engineering methodologies like ReDACT will enable additional experiments to further unravel the consequences of aneuploidy in development and disease. Chromosomal engineering to investigate the effects of aneuploidy. ( A ) ReDACT enables the targeted deletion of aneuploid chromosomes. ( B ) Loss of an extra copy of chromosome 1q compromises malignant growth. ( C ) MDM4 and BCL9 are dosage-sensitive drivers of chromosome 1q gain in cancer. ( D ) Chromosome 1q gain can be targeted therapeutically with UCK2-specific nucleotide analogs.
Type of Medium:
Online Resource
ISSN:
0036-8075
,
1095-9203
DOI:
10.1126/science.adg4521
Language:
English
Publisher:
American Association for the Advancement of Science (AAAS)
Publication Date:
2023
detail.hit.zdb_id:
128410-1
detail.hit.zdb_id:
2066996-3
detail.hit.zdb_id:
2060783-0
SSG:
11
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