In a lab-grown cell study focused on potential new treatment targets for halting the spread of most pancreatic cancers, Johns Hopkins Medicine scientists report they have found that a gene called KLF5 (Krueppel-like factor 5) fuels the growth of such spreading tumors not by acquiring abnormal changes in the cancer cells' DNA code itself but by altering chemical changes and organization of DNA, or epigenetics, that turns genes on and off.
"Epigenetic alterations are underappreciated as a major route to developing and fueling the growth of cancer metastasis," says Andrew Feinberg, M.D. , Bloomberg Distinguished Professor in the Johns Hopkins University schools of medicine, engineering and public health. Feinberg led researchers in 2017 to show that people with the most common form of pancreatic cancer had widespread epigenetic alterations, as opposed to new changes in the DNA code itself, or mutations, in their primary tumor that drove the cancer to metastasize to other parts of the body.
The new findings, which have implications in the search for treatments for pancreatic and other cancers, led them to pursue the current study, funded in part by the National Institutes of Health and described today in Molecular Cancer .
For the current study, the scientists aimed to find the most impactful genes associated with cancer cell growth. To do so, they used a gene-altering technology known as CRISPR to make cuts in DNA that silenced the genes in their investigative crosshairs. Once turned off, the genes that caused the largest shutdown of cell growth were considered to be most influential in cell growth had they been turned on.
The scientists found that KLF5 had the greatest effect specifically promoting the growth and invasion of metastatic cells, and that 10 of 13 people with pancreatic cancer had increased KLF5 gene expression in at least one metastatic lesion compared with the primary tumors.
The research team also did other experiments to validate KLF5's impact on metastatic cell growth and found that KLF5 controls the tight packaging of DNA, an epigenetic factor that enables genes to be turned on or off.
The scientists concluded that slight changes in KLF5 expression levels in the metastatic group of cells appeared to make relatively larger changes in the cells' ability to grow and spread. "This could suggest that, to develop treatments for pancreatic cancer metastasis, the gene may not need to be entirely shut down to have a positive effect," says Feinberg, who notes that several anti-cancer compounds targeting KLF5 are in development.
The scientists also found that KLF5 regulates at least two other genes, NCAPD2 and MTHFD1, in metastatic but not primary laboratory-grown pancreatic cancer cells. The two genes are known as epigenetic modifier genes, which turn genes on or off not through the genetic code but by adding chemical groups to the DNA and helping to alter its packaging.
"We are adding to evidence that cancer metastases are not caused by additional mutations in the primary cancer, but by additional epigenetic changes, enabling the cancer to thrive and grow," says first author Kenna Sherman, a graduate student in the Johns Hopkins Human Genetics and Genomics program. "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."
The research in this study was supported by the National Institutes of Health (CA54358, R01HG010889, R01HG013409, T32GM148383), a Celgene License Pathway Agreement and a gift from the friends and family of Jasmine Lampadarios.
Additional scientists who contributed to the study are Masahiro Maeda, Weiqiang Zhou, Jiaqi Cheng, Yuta Nihongaki, Adrian Idrizi, Rakel Tryggvadottir, Oscar Camacho, Michael Koldobskiy, Barbara Slusher and Hongkai Ji from Johns Hopins; Xingbo Shang and Andre Levchenko from Yale University; and Jimin Min and Anirban Maitra from NYU Langone Health.
DOI: 10.1186/s12943-026-02575-z
