Epigenetic Changes Fuel the Spread of Pancreatic Cancer
In a groundbreaking investigation conducted with lab-grown cells, researchers at Johns Hopkins Medicine have uncovered critical insights into how pancreatic cancer spreads. They discovered that a specific gene known as KLF5 (Krueppel-like factor 5) plays a significant role in promoting the growth of metastatic tumors. What’s particularly fascinating is that KLF5 does not initiate this process by causing mutations or abnormal changes in the DNA sequence itself. Instead, it influences the chemical modifications and structural organization of DNA—referred to as epigenetics—that regulate the activation and deactivation of genes.
"The significance of epigenetic alterations in fueling cancer metastasis is often underestimated," explains Dr. Andrew Feinberg, a Bloomberg Distinguished Professor who leads research at Johns Hopkins across multiple disciplines, including medicine, engineering, and public health. Back in 2017, Feinberg led a study demonstrating that individuals diagnosed with the most prevalent form of pancreatic cancer exhibited widespread epigenetic changes in their primary tumors, rather than fresh mutations, which were responsible for the cancer spreading to other areas of the body.
The recent findings are pivotal in the ongoing quest for effective treatments for pancreatic cancer and other malignancies. This study, partly supported by the National Institutes of Health, has been published in the journal Molecular Cancer.
In this current research endeavor, the team set out to identify the most influential genes connected to the growth of cancer cells. They employed a powerful gene-editing tool called CRISPR, which allows precise cuts in DNA. By silencing certain genes, they could determine which ones had the greatest effect on halting cell growth—thus identifying those that would be most critical if activated.
Their investigations revealed that KLF5 was particularly effective at fostering the growth and invasion of metastatic cancer cells. Notably, among 13 patients with pancreatic cancer, 10 showed elevated expression of the KLF5 gene in at least one metastatic site when compared to their primary tumors.
To further substantiate KLF5's role in promoting metastatic cell proliferation, the research team conducted additional experiments. They found that KLF5 is essential for maintaining the compact structure of DNA—a key epigenetic aspect that influences whether genes are turned on or off.
The scientists concluded that even minor fluctuations in KLF5 expression levels within these metastatic cells lead to considerably larger impacts on the cells’ capacity to grow and spread. This suggests that developing therapies targeting pancreatic cancer metastasis might not require completely shutting down KLF5; instead, modulating its activity could yield beneficial outcomes. Dr. Feinberg also mentioned that several anti-cancer agents aimed at KLF5 are currently under development.
Moreover, the research identified that KLF5 regulates at least two additional genes, NCAPD2 and MTHFD1, specifically in metastatic pancreatic cancer cells, but not in their primary counterparts. These genes are categorized as epigenetic modifiers, meaning they influence gene activity without altering the DNA sequence itself, primarily through the addition of chemical groups to the DNA, thereby affecting its packaging.
Kenna Sherman, the first author of the study and a graduate student in the Human Genetics and Genomics program at Johns Hopkins, stated, "We are contributing to the understanding that cancer metastases arise from epigenetic changes rather than merely additional mutations in the primary tumor, enabling the cancer to thrive and proliferate. KLF5 appears to be a master regulator that orchestrates these changes and impacts a pathway of genes linked to invasion and treatment resistance."
This research received support from the National Institutes of Health (grants CA54358, R01HG010889, R01HG013409, T32GM148383), a Celgene License Pathway Agreement, and a donation from the friends and family of Jasmine Lampadarios.
Additional contributors to this research include Masahiro Maeda, Weiqiang Zhou, Jiaqi Cheng, Yuta Nihongaki, Adrian Idrizi, Rakel Tryggvadottir, Oscar Camacho, Michael Koldobskiy, Barbara Slusher, and Hongkai Ji from Johns Hopkins; Xingbo Shang and Andre Levchenko from Yale University; along with Jimin Min and Anirban Maitra from NYU Langone Health.
DOI: 10.1186/s12943-026-02575-z
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