Researchers at the Hebrew University of Jerusalem (HU) discovered that changes in the processing of RNA molecules – and not genetic changes in the DNA – drive pancreatic ductal adenocarcinoma (PDA) tumors to become metastatic, spreading to other parts of the body.
This multinational lab study was conducted in collaboration with Sheba Medical Center at Tel Hashomer and Bar-Ilan University (BIU) in Ramat Gan; Cornell University and Cold Spring Harbor Laboratory in New York; and Toronto University in Canada.
Published in the prestigious journal Nature under the title “RBFOX2 modulates a metastatic signature of alternative splicing in pancreatic cancer,” the study was led by doctoral student Amina Jbara of Prof. Rotem Karni’s HU Faculty of Medicine research group.
Learning about pancreatic cancer
Pancreatic cancer accounts for about 3% of all cancers in Western countries and about 7% of all cancer deaths. It is slightly more common in men than in women. Fewer than one in 10 survive more than a few years. As one of the most lethal cancers, it is characterized by aggressive local invasion and metastatic spread. Although driver gene mutations are conserved during PDA progression, no specific mutation is correlated with the dissemination of metastases.
Evaluating about 400 PDA tumor samples, both metastatic and not, the researchers discovered that a central protein controlling RNA processing, RBFOX2, is degraded and present in much lower levels in metastases.
“Our unique findings demonstrate that the disappearance of RBFOX2 protein causes hundreds of genes to produce RNAs and proteins in a different way, which contributes to the invasive capabilities of the cancer cells.”
Rotem Karni
“Our unique findings demonstrate that the disappearance of RBFOX2 protein causes hundreds of genes to produce RNAs and proteins in a different way, which contributes to the invasive capabilities of the cancer cells,” Karni explained. “We found that restoring RBFOX2 to PDA metastatic cells inhibits the formation of metastases, while the elimination of RBFOX2 in non-metastatic PDA cells stimulates the formation of pancreatic cancer metastases.”
The study shows that the disappearance of RBFOX2 specifically affects a group of genes that control the organization of the cell skeleton and are important for the motility and invasive ability of the cells.
“For the first time, these research findings explain the molecular (non-genetic) basis by which pancreatic cancer cells become metastatic,” Karni said. “In addition, the findings offer two possible options for treatment of metastatic pancreatic cancer: either a known drug that inhibits a process that is affected by RBFOX2 or an RNA-based therapy that intervenes in the processing of specific RBFOX2-affected RNAs.”
While using a drug that is currently available to treat organ-transplant patients that inhibits the activity of this group of genes, the researchers found it is possible to delay the formation of pancreatic cancer metastases in a mouse model. In addition, by genetic intervention in RNA processing of RBFOX2-affected genes, the researchers showed that it is possible to cancel the metastatic ability of pancreatic cancer cells taken from patients so they cannot form metastases when transplanted into mice.
The study was funded by grants from the Alex U. Soyka Pancreatic Cancer Research grant (CFHU) and Israel Cancer Association (ICA).