March 23, 2023 -- An analysis of 400 pancreatic cancer tumor samples has linked a protein that controls RNA processing to the formation of metastases, suggesting that it may be possible to delay the spread of the cancer.
Evaluations of pancreatic cancer genomes have uncovered four genes that drive the initial formation of the solid tumor. However, while the mutations are conserved as the disease progresses, the analyses of the genomes have failed to reveal a genetic trigger for the development of metastases. The lack of a genetic driver of metastatic cancer has led researchers to look for other causes of disease progression.
Building on reports that RNA splicing, a step in protein production, may be involved in pancreatic cancer, researchers at Sheba Medical Center and Bar Ilan University in Israel, Cornell University and Cold Spring Harbor Laboratory in the U.S., and Toronto University in Canada initiated a study.
For the study, details of which were published in Nature, the collaborators looked at RNA-sequencing (RNA-seq) datasets from 395 pancreatic cancer samples. The datasets covered both metastatic and local disease. In people with metastatic cancer, a protein that controls RNA processing, RBFOX2, was degraded and found at much lower levels.
Overexpression of RBFOX2 in a patient-derived metastatic cell line reduced the potential of the cells to spread to new sites in vitro and in vivo. In contrast, metastatic potential increased when the protein was depleted in primary, local pancreatic tumor cell lines. The data suggest RBFOX2 suppresses metastases.
RNA-seq and splicing analysis of RBFOX2 target genes found the protein acts on genes that control the organization of the cell skeleton and influence the motility of cells. Rotem Karni, a professor at Hebrew University Faculty of Medicine, outlined the findings.
"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 said in a statement.
The analysis revealed gene enrichment in RHO GTPase, pathways for which pharmacological inhibitors already exist. The collaborators tested two inhibitors of the pathways, MBQ167 and azathioprine. In a mouse model, RAC1 blocker azathioprine, an immunosuppressant given to transplant patients, inhibited lung metastases. The researchers achieved similar results by genetically knocking out the RAC1 gene.
Based on the results, the researchers concluded that azathioprine and MBQ167 are good candidates for potential therapeutic intervention in metastatic pancreatic cancer.