Colon cancer cells that gain a single extra chromosome during tumor progression may, in rare cases, inhibit metastasis, rather than simply accelerate its development, according to research out of Cold Spring Harbor Laboratory in New York.

“We find no evidence to support the hypothesis that specific aneuploidies are universal metastasis promoters,” the researchers wrote in Developmental Cell.1 “Instead, the consequences of each aneuploidy are closely tied to the original tumor type.”

In experiments involving modified human colon cancer cells — each identical except for an extra copy of different chromosomes — the research team found that those harboring a surplus chromosome 5 behaved differently from the other trisomies studied. Single-chromosome gains in 12 cell lines inhibited (or had a minor effect on) invasiveness and cell motility, they said, while those carrying an extra chromosome 5 saw a strengthening in metastatic capability.

Anand Vasudevan, PhD, a postdoctoral research fellow and 1 of the paper’s authors, called the finding novel. “We don’t yet know how to personalize treatment based on chromosome 5 trisomies,” he wrote in an email to Cancer Therapy Advisor. “But, we’re now doing CRISPR screens to find out.”


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The editing tool will enable Dr Vasudevan and his colleagues screen through hundreds of genes to identify those that might serve as potential immunotherapy targets on chromosome 5 in the future. An initial gene panel of 24 genes, selected from literature reviews, he said, proved unsuccessful.

The loss or gain of extra copies of chromosomes occur frequently in cancer, some experts say, often as disease worsens. Long an area of intense research, aneuploidy is associated with up to 90% of solid tumors,2 Dr Vasudevan said, with the condition seen more often in some cancers than others. In glioblastoma, for example, an extra copy of chromosome 7 generally means a poor prognosis for patients, he said, as do high levels of aneuploidy in many other cancers.

The emerging research picture, however, remains complex. Not only do some tumors lack aneuploidy or have few extra chromosomal copies, others have a slew of mutations, said Jean Claude Zenklusen, PhD, who is the director of The Cancer Genome Atlas (TCGA) at the National Cancer Institute of the National Institutes of Health in Bethesda, Maryland. Still others, like ovarian cancers, are totally dependent on aneuploidy, he said, with “lots of copy number gains and chromosomes, but mutations — not so much.”

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Dr Zenklusen sees the Cold Spring Harbor study as part of the linear research stream that slowly moves science forward, rather than as a groundbreaking piece of work. He also voiced surprise at the investigators’ use of an older technology to isolate individual genes, which he called painful and laborious — or a “sledgehammer approach” compared with today’s newer techniques.

But, that’s not to say the study isn’t valid, he stressed, nor that the number of copy changes seen in a gene are unimportant. What’s needed is a better understanding of the nuances that occur as cells turn malignant, Dr Zenklusen said, with “some clear today and some less clear.” Moreover, the promise of an investigational treatment should be explained to patients with the use of more context, he added, so that patients know “we’re talking 15-to-20 years before our discoveries reach the clinic.”

References

  1. Vasudevan A, Baruah PS, Smith JC, et al. Single chromosmal gains can function as metastasis suppressors and promoters in colon cancer. Dev Cell. 2020;52(4):413-428.e6.
  2. Weaver, BA, Cleveland DW. The aneuploidy paradox in cell growth and tumorigenesis. Cancer Cell. 2008;14(6):431-433.