Mayo Clinic researchers say molecule linked to aggressive pancreatic cancer offers potential clinical advances

Mayo Clinic researchers have discovered an enzyme they say is tightly linked to how aggressive pancreatic cancer will be in a patient. They say that the study, published in Molecular Cancer Research, provides key insights into the most aggressive form of the disease. It also offers a number of possible future clinical advances, such as a way to gauge outcome in individual patients, and insight into potential therapies to shut down activity of the enzyme, known as Rac1b.

“The implication from our research is that Rac1b is activating unique pathways in pancreatic tumors that make this cancer aggressive. If we can therapeutically target that pathway, we may be able to have an impact on this very difficult-to-treat disease,” says the study’s senior investigator, Derek Radisky, PhD.

The RAC1 superfamily of proteins, which play important regulatory roles in cell growth and cell movement, have been implicated in other cancers, such as melanoma and non-small cell lung cancer, but until now it was not known that one sub-form (Rac1b) played a role in pancreatic cancer. A potential drug target would have to be found within the cancer-causing pathways activated by Rac1b, since the enzyme is difficult to target because it is involved in many normal biological processes, Dr. Radisky says. He and his colleagues are now working to uncover how Rac1b ramps up pancreatic cancer progression.

The team began its research by investigating why pancreatic cancer cells produce matrix metalloproteinases (MMPs), enzymes that break down the sticky adhesion molecules that keep cells glued together in a tissue, or in a tumor. MMPs allow cancer cells to migrate away from a tumor. Using a combination of human tissue biopsies, novel transgenic animal models, and cell culture studies, the researchers established a link between expression of MMP3 and activation of Rac1b. Then, using Mayo Clinic’s large panel of human pancreatic cancer biopsies, they found that expression levels of Rac1b were significantly associated with the cancer’s prognosis. They verified their findings by treating cultured pancreatic cancer cells with recombinant MMP3. They found this was sufficient to induce Rac1b and increased cancer invasiveness. Read the study abstract.