Researchers at the Hebrew University of Jerusalem have discovered that changes in the processing of RNA molecules – not genetic changes in DNA – cause pancreatic ductal adenocarcinoma (PDA) tumors to become metastatic, spreading to other parts of the body.

This multinational laboratory 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 the University of Toronto 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 PhD student Amina Djbara from the research group of the Faculty of Medicine of Prof. Rotem Carney.

Study of 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 deadliest types of cancer, it is characterized by aggressive local invasion and metastatic spread. Although driver genetic mutations are conserved during PDA progression, no specific mutation correlates with metastatic dissemination.

Evaluating around 400 PDA tumor samples, both metastatic and non-metastatic, the researchers found that a central protein that controls RNA processing, RBFOX2, is degraded and present at much lower levels in metastases.

"Our unique findings show that the disappearance of the RBFOX2 protein causes hundreds of genes to produce RNA and proteins in a different way, which contributes to the invasive capabilities of cancer cells." "We found that restoring RBFOX2 in metastatic PDA cells inhibited the formation of metastases, while elimination of RBFOX2 in non-metastatic PDA cells stimulated the formation of pancreatic cancer metastases," Carney explained.

The study shows that the loss of RBFOX2 specifically affects a group of genes that control the organization of the cytoskeleton and are important for cell motility and invasiveness.

"For the first time, these research findings explain the molecular (non-genetic) basis by which pancreatic cancer cells become metastatic." "In addition, the findings offer two possible treatment options for metastatic pancreatic cancer: either a known drug that inhibits a process affected by RBFOX2 or an RNA-based therapy that intervenes in the processing of specific RNAs affected by RBFOX2," Carney said.

While using a drug currently available to treat organ transplant patients that inhibits the activity of this group of genes, the researchers found that it was possible to delay the formation of pancreatic cancer metastases in a mouse model. In addition, by genetic intervention in the RNA processing of genes affected by RBFOX2, the researchers showed that it was possible to cancel the metastatic ability of pancreatic cancer cells taken from patients, so that they could not form metastases when transplanted into mice.