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surplus-chromosomes-may-fuel-tumor-growth-in-some-cancers

WASHINGTON — Some cancers are addicted to having extra chromosomes, a study in mice suggests.

Cells usually have just two copies of
each chromosome — one inherited from mom and one from dad. But about 90 percent
of cancer cells have additional chromosomes, a condition called aneuploidy.

Certain types of cancer cells often
carry a third copy of a particular chromosome or part of a chromosome. For
instance, more than half of colorectal
tumors
have a surplus chromosome 13, and more than 40 percent carry an
extra chromosome 7 or the long arm of chromosome 8 (SN: 5/31/18). Stocking spare copies of chromosomes has been
associated with poorer outcomes for patients compared with patients whose
cancers have the usual two copies.

It turns out that those extra doses of
genetic material are necessary
for the cancer cells to keep growing
, cancer geneticist Jason Sheltzer
reported December 11 at the joint annual meeting of the American Society for
Cell Biology and the European Molecular Biology Organization. Put another way,
cancer tumors are addicted to the bonus chromosomes, he says.


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The idea of “addicted” cancer cells
isn’t completely new. Scientists have known for decades that cancer cells can
be addicted to altered versions of certain genes, meaning that those genes are
required for the continued cancerous growth of the cells.

As for chromosomes, researchers have
speculated for more than a century that some cancers have particular chromosome
surpluses that spur growth. But the ability to specifically delete specific
chromosomes to test the idea is new, says Beth Weaver, a cancer cell biologist
at the University of Wisconsin–Madison,
who was not involved in the work.

In the new research, Sheltzer, of Cold
Spring Harbor Laboratory in New York, developed a method for purging extra
copies of whole chromosomes or parts of chromosomes from cells. A type of
ovarian cancer cell called A2780 carries an extra copy of the long arm of
chromosome 1, known as 1q. Sheltzer used his manipulation technique to remove
the extra copy of 1q from the cancer cells, then compared how well the original
and 1q-deprived cancer cells grew in lab dishes and when transplanted into mice.

Cells with the surplus chromosome arm
formed many large colonies in dishes and grew into tumors in mice. But cells
that lost 1q “barely grew at all,” Sheltzer said. “They’ve almost entirely lost
their ability to exhibit malignant growth.” What’s more, cells from which the
extra arm had been removed later somehow regained another copy, restoring the
cells’ growth. “These cells for some reason really, really, really want to have
three copies of this chromosome arm,” he said.

That result is persuasive, says cancer
cell biologist Adrian Saurin of the University of Dundee in Scotland. “That’s a
real sign of addiction, if you take it away and they manage to get it back
again,” he says.

The idea that cancer cells can be
addicted to genes forms the basis for many targeted cancer therapies, which
interfere with the action of genes driving the cancer. Chromosomes, however,
contain thousands of genes, so narrowing down which of those many genes or
combination of genes is the source of addiction is much more complicated.

But finding out which genes turn cancer
cells into addicts is necessary if researchers are ever going to develop
treatments to negate the effect of bonus chromosomes, Saurin says. “We probably
need to understand a lot more of the biology [of cancer cells] before [the new
research] becomes clinically useful,” he says. “But I could see it in the
future.”

Sheltzer took a step toward pinpointing
why 1q has ovarian cancer cells hooked. The chromosome arm contains more than
1,000 genes, but Sheltzer found a likely culprit in the gene MDM4. That gene produces a protein that
inhibits activity of p53, a protein that helps prevent cancer. With more MDM4
protein around, p53’s tumor-suppressing activity is diminished, allowing cancer
cells to grow unchecked, Sheltzer reasoned.

To test that idea, he used the
gene editor CRISPR/Cas9
to remove the MDM4
gene from the surplus 1q (SN: 8/14/19).
Cells lacking the third copy of MDM4 formed
fewer colonies in lab dishes than cells with three copies, he found. But further
experiments showed that gene isn’t the only one spurring the growth.

For now, the work is still preliminary,
and Sheltzer hopes to do similar experiments with other types of cancers to
determine whether aneuploidy addiction is common to all cancers.

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