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New gene discovered that stops the spread of deadly cancer

Scientists in Reuben Shaw's lab 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–the researchers are able to explain why some tumors are more prone to spreading than others. The newly discovered pathway, detailed in the journal Molecular Cell, may also help scientists understand and treat the spread of melanoma and cervical cancers.

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.

“Lung cancer, even when it’s discovered early, is often able to metastasize almost immediately and take hold throughout the body,” says Shaw, professor in Salk’s Molecular and Cell Biology Laboratory and a Howard Hughes Medical Institute early career scientist. “Now, through this work, we are beginning to understand why some subsets of lung cancer are so invasive.”

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), allowing cancer cells to begin migration.

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 (or STK11). Cancers missing LKB1 often spread rapidly through the body. However, no one knew how LKB1 and focal adhesions were connected.

Focal adhesion complexes (bright green) are typically large and sticky, anchoring a cell into place (left). When the gene DIXDC1 is knocked out, focal adhesion complexes instead become small and numerous, readying cancer cells to move into the bloodstream and become metastatic (right)

Focal adhesion complexes (bright green) are typically large and sticky, anchoring a cell into place (left). When the gene DIXDC1 is knocked out, focal adhesion complexes instead become small and numerous, readying cancer cells to move into the bloodstream and become metastatic (right).

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, allowing the tumor cells to escape the lungs, survive travel through the bloodstream and dock at organs throughout the body.

Tumors turn off this stay-put signal by either inhibiting DIXDC1 directly or deleting LKB1. The team also found that the addition of DIXDC1 did indeed blunt the ability of cancer cells with low levels of DIXDC1 to be metastatic in vitro and in vivo.

“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.