Lung cancer cells as seen under a microscope. Image: Yale Rosen/flickr |
MIT
cancer biologists have identified a genetic change that makes lung tumors more
likely to spread to other parts of the body. The finding offers new insight
into how lung cancers metastasize and could help identify drug targets to
combat metastatic tumors, which account for 90% of cancer deaths.
The
researchers, led by Tyler Jacks, director of the David H. Koch Institute for
Integrative Cancer Research at MIT, found the alteration while studying a mouse
model of lung cancer. They then compared their mouse data to genetic profiles
of human lung tumors and found that reduced activity of the same gene, NKX2-1,
is associated with higher death rates for lung-cancer patients.
This
study represents an important step in understanding how changes that disable
this gene would make tumors more aggressive, says Monte Winslow, a senior
postdoctoral associate in Jacks’ lab and lead author of a paper on the work appearing
online in Nature.
Understanding
the role of NKX2-1 may help scientists pursue drugs that could counteract its
loss. Right now, “the sad reality is that if you could tell a patient whether
their cancer has turned down this gene, you would know they will have a worse
outcome, but it wouldn’t change the treatment,” Winslow says.
Controlling the spread
Winslow and his colleagues at the Koch Institute studied mice that are
genetically programmed to develop lung tumors. The mice’s lung cells can be
induced to express an activated form of the cancer-causing gene Kras, and the tumor
suppressor gene p53 is deleted. While all of those mice develop lung tumors,
only a subset of those tumors metastasizes, suggesting that additional changes
are required for the cancer to spread.
The
researchers analyzed the genomes of metastatic and non-metastatic tumors in
hopes of finding some genetic differences that would account for the
discrepancy. The absence of NKX2-1 activity in metastatic tumors was the most
striking difference, Winslow says.
The
NKX2-1 gene codes for a transcription factor—a protein that controls expression
of other genes. Its normal function is to control development of the lung, as
well as the thyroid and some parts of the brain. When cancerous cells turn down
the expression of the gene, they appear to revert to an immature state and gain
the ability to detach from the lungs and spread through the body, seeding new
tumors.
Once
the researchers identified NKX2-1 as a gene important to metastasis, they
started to look into the effects of the genes that it regulates. They zeroed in
on a gene called HMGA2, which had been previously implicated in other types of
cancer. It appears that NKX2-1 represses HMGA2 in adult tissues. When NKX2-1 is
shut off in cancer cells, HMGA2 turns back on and helps the tumor to become
more aggressive.
They
also found that human tumors with NKX2-1 missing and HMGA turned on tended to
be metastatic, though not all metastatic tumors fit that profile.
Other
researchers have reported that in about 10% of lung cancers, there are too many
copies of NKX2-1—the opposite of what the MIT team found in this study. That is
not uncommon, says David Mu, an associate professor of pathology at Penn State
Univ., who also studies lung cancer.
“Many
cancer genes exhibit this kind of dual personality,” says Mu, who was not
involved in this study. “It’s important to figure out what’s happening in
different contexts.”
Targeting genes
It would be difficult to target NKX2-1 with a drug because it’s much harder to
develop drugs that turn a gene back on than shut it off, Winslow noted. A more
promising possibility is targeting HMGA2 or other genes that NKX2-1 represses.
Jacks’
lab is now looking at other types of cancer, to see if NKX2-1 or HMGA2 have the
same role in other metastatic cancers. “It’s great to find something that’s
important in lung cancer metastasis, but it would be even better if it
controlled metastasis in even a subset of other cancer types,” Winslow says.
