Scientists at Johns Hopkins Medicine have pinpointed the gene KLF5 as a key driver of pancreatic cancer metastasis through epigenetic changes rather than DNA mutations. Using CRISPR technology, researchers found that KLF5 promotes tumor growth and invasion by altering DNA packaging and activating other cancer-related genes. The findings, published in Molecular Cancer, suggest potential new treatment targets.
Researchers at Johns Hopkins Medicine discovered that the gene KLF5 plays a central role in the spread of pancreatic cancer. In lab-grown metastatic cells, KLF5 boosted tumor growth and invasion by reshaping DNA organization and chemical modifications, which control gene activity. This epigenetic mechanism differs from traditional DNA mutations, as noted by Andrew Feinberg, M.D., Bloomberg Distinguished Professor at Johns Hopkins. “Epigenetic alterations are underappreciated as a major route to developing and fueling the growth of cancer metastasis,” Feinberg said. The team builds on their 2017 findings that epigenetic changes drive pancreatic cancer progression in primary tumors. Using CRISPR gene-editing, the scientists systematically silenced genes to identify those critical for cancer cell growth. KLF5 emerged as the top candidate, with the strongest impact on metastatic cells. In patient samples, 10 of 13 individuals showed elevated KLF5 activity in metastatic tumors compared to original ones. Even modest increases in KLF5 activity enhanced cancer cell proliferation and spread. KLF5 also regulates genes like NCAPD2 and MTHFD1, which modify epigenetics, but only in metastatic pancreatic cancer cells. “KLF5 seems to be a master gene that drives such changes and impacts a pathway of genes known to control invasion and the ability to resist treatments,” said first author Kenna Sherman, a graduate student in Johns Hopkins' Human Genetics and Genomics program. Feinberg noted that experimental drugs targeting KLF5 are in development, potentially requiring only partial inhibition for effect. The study received support from the National Institutes of Health and others.
