I
still recall my disappointment one day in 2015. I received the
tumor DNA sequencing results for one of my patients, whose
cancer had spread from her lungs to her brain. I saw not a sin-
gle genetic alteration that could point us to a targeted treat-
ment approach. Yet something else caught my eye in the data:
there were numerous changes in the structures and numbers of
nearly every chromosome.
Instead of having two copies of each chromosome, as is typi-
cal for normal cells, the cancer cells had anywhere from one to
as many as five or six copies; and sometimes there were parts of
chromosomes on their own, in one or multiple copies. The phe-
nomenon that produces such genomic chaos is known as chromo-
somal instability (CIN). Cancer researchers and clinicians have
long appreciated CIN as a hallmark of advanced and metastatic
cancers; and yet I did not expect to see it present to this extent in
my 59-year-old patient, given her recent cancer diagnosis and the
fact that CIN is known to arise progressively over time.
To oncologists’ frustration, there are no good therapies that
target cancers with CIN. Patients may simply receive multiple
rounds of systemic chemotherapies and radiation. My patient was
no different; the only option available to treat her metastases was
radiation to the brain, which runs the risk of neurological toxicity,
sometimes resulting in memory loss or other cognitive deficits,
among other side effects.
This dilemma resonated with me given my background as a
cell biologist. A decade earlier, my doctoral work had centered
on trying to understand how chromosomes in normal cells are
evenly distributed between the two daughter cells during mitosis.
The process is so intricate and so frequent—in many tissues, cell
division happens faithfully and on a daily basis—that evolution
has devised multiple backup mechanisms to ensure it takes place
without errors. On the rare occasion that errors do occur, cells
with abnormal chromosome numbers are rapidly cleared. But
cancer is different. Tumor cells are remarkably tolerant of chro-
mosomal abnormalities, and such large-scale genomic changes
often go hand in hand with disease progression. Yet, whether CIN
plays an active role in promoting cancer progression and metas-
tasis has remained unclear, as have the mechanisms by which
such gross chromosomal abnormalities might exert these effects.
A few years ago, I set out to determine if CIN drives cancer pro-
gression or if it is simply a separate phenomenon that goes along for
the ride. To do this, I teamed up with Lewis Cantley, who at the time
was leading the Meyer Cancer Center at Weill Cornell Medicine and
is now at the Dana-Farber Cancer Institute. We genetically manipu-
lated various metastatic, chromosomally unstable cancer cells, reduc-SPRING 2022 | THE SCIENTIST 31CREDIT LINEMODIFIED FROM © ISTOCK.COM,
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