Johns Hopkins scientists have pinpointed an epigenetic “master gene” that helps pancreatic cancer spread, opening a potential new path for treatments that target how DNA is controlled rather than the DNA code itself.
Pancreatic cancer is one of the deadliest cancers, largely because it is often discovered only after it has spread to other parts of the body. Now, Johns Hopkins Medicine researchers have identified a powerful driver of that spread — not in the DNA code itself, but in the way DNA is packaged and controlled.
In a new lab study of human pancreatic cancer cells, published in the journal Molecular Cancer, the team found that a gene called KLF5 fuels the growth and invasion of metastatic tumors by reshaping the epigenetic landscape. Epigenetics refers to chemical tags and structural changes that sit on top of DNA and control which genes are turned on or off, without altering the underlying genetic sequence.
“Epigenetic alterations are underappreciated as a major route to developing and fueling the growth of cancer metastasis,” Andrew Feinberg, a Bloomberg Distinguished Professor in the Johns Hopkins University schools of medicine, engineering and public health who has long studied epigenetics and cancer, said in a news release.
Metastasis is the process by which cancer cells break away from a primary tumor and colonize distant organs.
Feinberg and colleagues previously showed in 2017 that people with the most common form of pancreatic cancer had widespread epigenetic alterations in their primary tumors, rather than new DNA mutations, that appeared to drive metastasis. Those findings prompted the current study.
To zero in on the most influential genes behind cancer cell growth, the researchers turned to CRISPR, a gene-editing tool that can precisely cut DNA. They systematically used CRISPR to switch off selected genes in lab-grown pancreatic cancer cells and watched what happened.
If shutting down a gene caused cancer cell growth to stall, that gene was flagged as a key player when active. Among all the genes tested, KLF5 stood out. Silencing KLF5 had the strongest effect in slowing the growth and invasion of metastatic pancreatic cancer cells.
The team then looked at tissue from people with pancreatic cancer and found that 10 of 13 patients had higher KLF5 activity in at least one metastatic lesion compared with their primary tumor. That pattern suggested that KLF5 ramps up specifically in cells that have spread.
Further experiments showed that KLF5 helps control how tightly DNA is packaged inside cells. DNA is wrapped around proteins and folded into complex structures; when it is tightly packed, genes are generally turned off, and when it is more open, genes are easier to activate. By influencing this packaging, KLF5 acts as an epigenetic regulator, turning sets of genes on or off in ways that favor cancer growth and movement.
The scientists concluded that even modest increases in KLF5 levels in metastatic cells led to disproportionately large boosts in their ability to grow and spread. That sensitivity could be good news for drug development.
“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,” added Feinberg, who pointed out that several anti-cancer compounds aimed at KLF5 are already in development.
Being able to dial down KLF5 activity, rather than eliminate it completely, might make future therapies more feasible and potentially safer.
The study also traced KLF5’s influence to at least two other genes, NCAPD2 and MTHFD1, but only in metastatic pancreatic cancer cells, not in primary tumor cells grown in the lab. Both of these genes are known as epigenetic modifiers. Instead of changing DNA sequences, they add chemical groups to DNA and help reshape how it is packaged, further adjusting which genes are active.
The work strengthens a growing view of how cancer spreads, according to first author Kenna Sherman, a graduate student in the Johns Hopkins Human Genetics and Genomics program.
“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,” she said in the news release. “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.”
That idea marks a shift from the traditional focus on DNA mutations alone. For decades, cancer research has largely centered on identifying and targeting specific genetic mutations that drive tumor growth. The Johns Hopkins team’s work underscores that changes in gene regulation and DNA packaging can be just as important, especially for metastasis.
If epigenetic changes are central to how pancreatic cancer spreads and resists therapy, they may also offer new vulnerabilities. Drugs that target epigenetic regulators are already used in some blood cancers, and researchers are exploring similar strategies for solid tumors. KLF5 and the network of genes it controls could become part of that expanding toolkit.
The current study was done in lab-grown human pancreatic cancer cells, so more research is needed before any KLF5-targeting therapy reaches patients. Next steps are likely to include testing KLF5 inhibitors in animal models of pancreatic cancer, mapping in more detail how KLF5 interacts with NCAPD2, MTHFD1 and other epigenetic regulators, and exploring whether similar mechanisms operate in other cancer types.
Pancreatic cancer remains a major challenge, with low survival rates and few effective options once the disease has spread. By revealing how an epigenetic “master gene” helps metastatic cells grow, the Johns Hopkins team has opened a new line of attack that could one day help slow or stop this aggressive cancer at its most dangerous stage.
Source: Johns Hopkins Medicine