Researchers have known for some time about the DNA mutations that lead healthy pancreatic cells to turn cancerous. What was not understood is how pancreatic cancer cells metastasize and invade other organs.
On March 22, the peer-reviewed journal Nature published a new study led by Israeli researchers at The Hebrew University of Jerusalem that explains the mechanism for metastasis. The research concluded that the spread of pancreatic cancer throughout the body is due to changes to the composition of the initial tumors’ RNA molecules, which translate instructions from DNA for protein synthesis in cells.
The good news is that at least one drug already exists that could potentially address the problems with the RNA and eventually help pancreatic cancer patients.
Pancreatic cancer accounts for three percent of all cancer cases and seven percent of all cancer deaths in the United States. The average lifetime risk of getting pancreatic cancer is 1 in 64, according to the American Cancer Society. The disease is seldom detected in its early stages, when it is most curable, due to lack of symptoms until it has spread. As a result, it is the most lethal cancer, with overall five-year survival rates at just 7%, according to the Mayo Clinic.
The study was led by doctoral candidate Amina Jbara of the department of biochemistry and molecular biology and a member of Prof. Rotem Karni‘s lab. Colleagues from Sheba Medical Center and Bar-Ilan University, Cornell University and Cold Spring Harbor Laboratory in the United States, and the University of Toronto in Canada were also involved.
“We analyzed tumor samples from around 400 patients with pancreatic cancer. Half of the tumors were primary tumors, which means they were in the very early stages of the disease and were limited to the pancreas. The other half were from tumors that had already metastasized to other organs,” Karni told The Times of Israel.
The team discovered that the RNA in primary tumors was different from the RNA in metastasized tumors because of a central protein, RBFOX2, that controls RNA processing. RBFOX2 is a regulator of a mechanism called splicing, which can change the genetic information encoded within RNA molecules.
“We found that RBFOX2 is degraded and present in much lower levels in metastases. Conversely, RBFOX2 is not degraded in primary tumors,” Karni said.
“We know that metastatic cells know how to degrade RBFOX2, but not exactly how. But when this protein is lost, this changes the composition of hundreds of RNA molecules and eventually, of course, hundreds of protein molecules,” he added.
The research process involved taking metastatic cells from a human patient and artificially re-expressing RBFOX2 into them. This stopped the cells from turning into metastases once they were introduced into mice. Conversely, the scientists took primary tumor cells from a patient and artificially silenced RBFOX2, turning those cells into metastatic ones.
Prof. Barak Rotblat, who studies the molecular biology of cancer at Ben-Gurion University of the Negev, praised the “elegant molecular biology techniques” used in the study.
“In my opinion, this type of research is how science unravels new aspects of cancer biology essential for finding new therapies. There are not many examples of such deep and comprehensive work showing splicing regulation in cancer in one paper,” Rotblat told The Times of Israel.
When asked whether the new study shines any light on any other types of cancer, Karni was careful to note that so far the loss of RBFOX2 happens only with pancreatic cancer metastases. Notably, the opposite happens with some other malignancies, such as breast cancer, where the protein is highly expressed.
A second significant finding reported in the paper may lead to a new weapon in the arsenal against pancreatic cancer.
“We also found that RBFOX2 controls around 100 genes that are associated with the cells’ skeletal organization and their ability to move faster and create tumors in other organs,” Karni said.
Critically, a different protein that RBFOX2 activates controls this skeletal organization. Fortunately, a drug already exists that successfully targets this other protein. The drug is called azathioprine (brand name Imuran), and it is approved for use as an immunosuppressant for organ transplant patients.
“If we use this drug, we could inhibit metastases in cells that have lost RBFOX2,” Karni said.
He reported that he has already been approached by pancreatic cancer patients wanting to know when the drug will be made available for them.
“First of all, we are researchers, not clinicians. But we are now talking with our collaborators in medical centers to convince them to start a clinical trial with either azathioprine or similar drugs that are not yet approved,” Karni said.