NEW GENE DISCOVERED THAT STOPS SPREAD OF CANCER
Scientists at the Salk
Institute have identified a gene responsible for stopping the movement of
cancer from the lungs to other parts of the body, indicating a new way to fight
one of the world's deadliest cancers.
By identifying the
cause of this metastasis -- which often happens quickly in lung cancer and
results in a bleak survival rate -- Salk scientists are able to explain why
some tumors are more prone to spreading than others. The newly discovered
pathway, detailed today in Molecular Cell, may also help
researchers understand and treat the spread of melanoma and cervical cancers.
"Lung cancer,
even when it's discovered early, is often able to metastasize almost
immediately and take hold throughout the body," says Reuben J. Shaw, Salk
professor of molecular and cell biology and a Howard Hughes Medical Institute
early career scientist. "The reason behind why some tumors do that and
others don't has not been very well understood. Now, through this work, we are
beginning to understand why some subsets of lung cancer are so invasive."
Lung cancer, which
also affects nonsmokers, is the leading cause of cancer-related deaths in the
country (estimated to be nearly 160,000 this year). The United States spends
more than $12 billion on lung cancer treatments, according to the National
Cancer Institute. Nevertheless, the survival rate for lung cancer is dismal: 80
percent of patients die within five years of diagnosis largely due to the
disease's aggressive tendency to spread throughout the body.
To become mobile,
cancer cells override cellular machinery that typically keeps cells rooted
within their respective locations. Deviously, cancer can switch on and off
molecular anchors protruding from the cell membrane (called focal adhesion
complexes), preparing the cell for migration. This allows cancer cells to begin
the processes to traverse the body through the bloodstream and take up
residence in new organs.
In addition to
different cancers being able to manipulate these anchors, it was also known
that about a fifth of lung cancer cases are missing an anti-cancer gene called
LKB1 (also known as STK11). Cancers missing LKB1 are often aggressive, rapidly
spreading through the body. However, no one knew how LKB1 and focal adhesions
were connected.
Now, the Salk team has
found the connection and a new target for therapy: a little-known gene called
DIXDC1. The researchers discovered that DIXDC1 receives instructions from LKB1
to go to focal adhesions and change their size and number.
When DIXDC1 is
"turned on," half a dozen or so focal adhesions grow large and
sticky, anchoring cells to their spot. When DIXDC1 is blocked or inactivated,
focal adhesions become small and numerous, resulting in hundreds of small
"hands" that pull the cell forward in response to extracellular cues.
That increased tendency to be mobile aids in the escape from, for example, the
lungs and allows tumor cells to survive travel through the bloodstream and dock
at organs throughout the body.
"The
communication between LKB1 and DIXDC1 is responsible for a 'stay-put' signal in
cells," says first author and Ph.D. graduate student Jonathan Goodwin.
"DIXDC1, which no one knew much about, turns out to be inhibited in cancer
and metastasis."
Tumors, Shaw and
collaborators found in the new research, have two ways to turn off this
"stay-put" signal. One is by inhibiting DIXDC1 directly. The other
way is by deleting LKB1, which then never sends the signal to DIXDC1 to move to
the focal adhesions to anchor the cell. Given this, the scientists wondered if
reactivating DIXDC1 could halt a cancer's metastasis. The team took metastatic
cells, which had low levels of DIXDC1, and overexpressed the gene. The addition
of DIXDC1 did indeed blunt the ability of these cells to be metastatic in vitro
and in vivo.
"It was very,
very surprising that this gene would be so powerful," says Goodwin.
"At the start of this study, we had no idea DIXDC1 would be involved in
metastasis. There are dozens of proteins that LKB1 affects; for a single one to
control so much of this phenotype was not expected."
Right now, there is no
specific treatment for cancers harboring LKB1 or DIXDC1 alterations, but those
with a deletion of either gene would likely see results from cancer drugs that
target the focal adhesions, says Shaw.
"The good news is
that this finding predicts that patients missing either gene should be
sensitive to new therapies targeting focal adhesion enzymes, which are
currently being tested in early-stage clinical trials," says Shaw, who is
also a member of the Moores Cancer Center and an adjunct professor at the
University of California, San Diego.
"By identifying
this unexpected connection between DIXDC1 and LKB1 in certain tumors, we have
expanded the potential patient population that may be good candidates for these
therapies," adds Goodwin.
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