MICAL2 enzyme found to promote tumor growth in pancreatic cancer

Pancreatic cancer kills 50,000 people each year, according to the National Cancer Institute, and there are few effective treatment options for the disease. In a new study, researchers at University of California San Diego School of Medicine have discovered that an enzyme called MICAL2 promotes tumor growth and spread in pancreatic ductal adenocarcinomas (PDAC), the most common form of pancreatic cancer. The study will be published on January 2, 2025 in Cancer Research, a journal of the American Association for Cancer Research.

Normally, MICAL2 plays an important role in cell migration and morphology. But when the researchers measured gene expression in PDAC tumor cells, they found that an excessive amount of the enzyme was being produced compared with non-diseased cells -; the first time MICAL2 has been experimentally linked to pancreatic cancer.

They also found that:

• Among patients undergoing surgery to remove their PDAC tumors, those with low MICAL2 expression in their tumor cells survived about twice as long as those whose tumor cells produced more of the enzyme, suggesting that MICAL2 may be involved in progressing the disease to an advanced stage.
• MICAL2 appears to supercharge the KRAS signaling pathway, which regulates cell growth, proliferation, and death and is known to be the primary driver of pancreatic tumor growth and the spread of the cancer to other tissues in the body. Silencing the MICAL2 gene in PDAC cells dramatically slowed the activity of the KRAS signaling pathway.
• When tumor cells are deficient in MICAL2, the KRAS signaling pathway is unable to harvest nutrients that lead to tumor growth.
• MICAL2 expression promotes tumor cell division, migration and the invasion of healthy tissue.

The findings suggest that MICAL2 could be a promising target for PDAC drug therapies, according to senior author Andrew Lowy, M.D., professor and division chief of surgical oncology at UC San Diego School of Medicine and associate clinical director for surgery at UC San Diego Moores Cancer Center.

Pancreatic cancer has the highest mortality rate of any common cancer and thus current treatments are woefully inadequate. We believe it will be possible to target MICAL2 with drugs as it is an enzyme in a class of proteins against which inhibiting drugs have been successfully made to treat other human diseases. We are now working to identify candidate drugs to begin the journey toward blocking MICAL2 function in pancreatic cancer."

Andrew Lowy, M.D., professor and division chief of surgical oncology, UC San Diego School of Medicine