Scientists at Cold Spring Harbor Laboratory have discovered a key biological mechanism that drives the spread of pancreatic cancer and helps explain why one of the most common forms of the disease is so deadly.
The researchers, in the just-released issue of the journal Cell, describe how working with tiny pancreatic organoids — miniature living models of the pancreas — led to their significant step in understanding DNA sequences that underlie the spread of pancreatic ductal carcinoma.
Cancer of the pancreas has the reputation of being one of the most lethal because of its overwhelming tendency to metastasize, spreading to sites beyond the gland itself, researchers said.
Pancreatic ductal cancer, a widely diagnosed form of the disease, often is called a “silent killer” because it produces no overt symptoms in its early development.
There is no method of routine screening to detect it and by the time most of these cancers are found, the disease has spread elsewhere in the body.
Cold Spring Harbor Laboratory scientists in the lab of Dr. David Tuveson, director of cancer therapeutics, unmasked one of the cancer’s longest-held secrets: Pancreatic cancer spreads because metastatic cells carry short sequences of DNA, called enhancers, that drive the cancer’s wanderlust.
Further analyses showed that a protein called FOXA1, active during normal embryonic development, was key in pancreatic cancer’s spread by binding to the enhancers.
These DNA enhancers are not active in early-stage pancreatic tumor cells, but are switched on as tumors grow and transform. They are abundant in recurrent pancreatic cancers, scientists said.
“We show that to metastasize, the cell has to change. In effect, its whole telecommunications network — its enhancers — are being reprogrammed,” Dr. Christopher Vakoc, a co-author of the study, said in a statement.
The team was able to decipher the role that the enhancers play by developing organoids that were models of both early-stage tumor cells and metastatic ones, he said.
In the laboratory, organoids are small, glistening spheres, each about the size of the period at the end of this sentence.
The miniature models allow researchers to understand why the cancer forms in the first place and how it receives genetic messages to spread.
“The discovery could have major implications for understanding and treating pancreatic cancer. By understanding the biochemical changes that trigger metastasis, eventually researchers will be able to screen potential drugs to suppress these changes,” said Kerri Kaplan, president and chief executive of The Lustgarten Foundation in Woodbury, which supports research efforts into the diagnosis, treatment and cure of pancreatic cancer.
While the new analsyis shines a spotlight on the mystery of metastasis, it is not yet known if similar enhancers explain why other forms of cancer spread, said Dr. Chang-Il Hwang, a postdoctoral fellow at Cold Spring Harbor Laboratory and member of the research team.
“We don’t have the experimental evidence to support that idea,” Hwang said. “We believe it’s highly possible, but has to be experimentally shown.”
Tuveson, also director of research for The Lustgarten Foundation, has long said that cancer of the pancreas is one of the most confounding human diseases. Only 7 percent of patients survive five years after diagnosis.
This year, the cancer is expected to be diagnosed in about 53,070 people nationwide — about 27,670 men and 25,400 women, according to the American Cancer Society.