In a new study published today in the journal Nature, a team of scientists led by researchers from the Hebrew University of Jerusalem 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.
This multinational study was conducted in collaboration with Sheba Medical Center and Bar Ilan University in Israel, Cornell University and Cold Spring Harbor Laboratory in the United States, and Toronto University in Canada. The study was led by doctoral student Amina Jbara of Professor Rotem Karni’s research group at the Hebrew University Faculty of Medicine.
Evaluating roughly four hundred PDA tumor samples, both non-metastatic and metastatic, the researchers discovered that a central protein that controls 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,” Professor Rotem 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, which control the organization of the cell skeleton and are important for the motility and invasive ability of the cells. Professor Rotem Karni explains, "For the first time, these research findings explain the molecular (non-genetic) basis by which pancreatic cancer cells become metastatic. In addition, these 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 and 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. Moreover, by genetic intervention in RNA processing of RBFOX2-affected genes, the researchers showed 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: Alex U. Soyka Pancreatic Cancer Research grant (CFHU), Israel Cancer Association (ICA) - 20220038, Israel Science Foundation (ISF) - 1510/17, United States - Israel Binational Science Foundation (BSF) - 2021108 [R. Karni] and Israel Ministry of Science, Zvi Yanai Ph.D. and post-doctoral fellowship program for outstanding minority students [A. Jbara].