Princeton scientists used 3D lab-grown breast tumors to uncover how fat-rich diets may help aggressive cancers invade nearby tissue. The work offers new clues about diet, tumor behavior and future treatment strategies.
A new Princeton University study adds weight to concerns that high-fat diets can do more than just feed tumors — they may help some of the most aggressive breast cancers become better at spreading.
Using sophisticated three-dimensional models of triple negative breast cancer, researchers found that when tumors were bathed in fat-rich nutrients, their structure changed in ways that are linked to invasion and metastasis. Instead of staying compact, the tumors sprouted hollow, finger-like branches that pushed into their surroundings.
The work, published March 3 in the journal APL Bioengineering, offers fresh insight into why patients with high-fat diets often have worse cancer outcomes and suggests new directions for therapies that target how tumors interact with their environment.
Triple negative breast cancer is one of the most difficult forms of the disease to treat because it does not respond to many standard hormone-based or targeted therapies. Understanding what makes these tumors more or less aggressive is a major focus of current research.
In the new study, the Princeton team grew hundreds of tiny 3D tumors over several years, using cells from triple negative breast cancer. Instead of growing the cells in a flat dish, they embedded them in a gel-like material and flowed human-like plasma through the system. This setup, called a 3D microfluidic model, allowed the researchers to simulate different “diets” by changing the mix of nutrients in the fluid.
They tested conditions that mimicked high levels of insulin, glycerol, ketones and fat, as well as a baseline nutrient mix. For most of these diets, the tumors grew but stayed relatively compact and rounded.
The high-fat condition was different.
When the tumors were exposed to fatty acids and cholesterol, they began forming small, hollow appendages that extended outward from the main mass. These branching structures are a hallmark of aggressive cancers that are preparing to invade nearby tissue and eventually spread through the body.
The visual pattern fits with the origin of the word cancer itself, as principal investigator Celeste Nelson explained.
“That’s where the name cancer comes from, crab-like,” Nelson, the Wilke Family Professor in Bioengineering and a professor of chemical and biological engineering, said in a news release. “Aggressive cancers have these tendrils, and it’s the leading edges that end up invading into our normal tissues and making it into either a lymphatic or a blood vessel and escaping and metastasizing.”
Even though the high-fat tumors did not grow faster than those in other conditions, their architecture shifted in a way that signals danger. Cells began migrating away from the tumor core toward the edges, where they are more likely to break free and travel.
On the molecular level, the researchers also saw increased activity of a gene called MMP1 in the high-fat condition. MMP1 is associated with breaking down collagen, a key component of the tissue that surrounds tumors. Higher MMP1 activity was strongly linked to the structural changes in the tumors.
The team suspects that fat in the tumor environment may be driving this gene activity, helping the cancer chew through nearby tissue and open paths for invasion. However, they have not yet proven that fat directly causes the MMP1 increase, and future experiments will be needed to test that idea more rigorously. One next step could be to see what happens when MMP1 is blocked in tumors exposed to high-fat conditions.
The findings do not necessarily apply to all cancers, and the researchers caution against overgeneralizing. Still, the work provides a clearer biological link between dietary fat and tumor aggressiveness in this particularly hard-to-treat breast cancer subtype.
The study also delivered a surprise about ketogenic diets, which are high in fat and very low in carbohydrates. Some past animal studies have suggested that ketogenic diets can slow tumor growth, raising hopes that they might help cancer patients.
In the Princeton experiments, the team created a nutrient mix designed to mimic a ketogenic diet and flowed it through the 3D tumor models. The tumors in this condition did not look healthier or less invasive than those in the baseline condition, although the researchers note that their findings here were limited.
“We were expecting a ketogenic diet to be protective,” Nelson added. “Yet we didn’t see that here. And it tells us a few possible things. One is that, for this particular type of cancer, maybe a ketogenic diet could be protective, but it operates through other cells that we don’t have in this particular model.”
That caveat highlights both the power and the limits of the 3D model. Compared with traditional two-dimensional cell cultures, which grow on stiff plastic surfaces and are fed simple sugar-based solutions, the microfluidic system is far more realistic. It captures the three-dimensional structure of tumors and allows scientists to adjust both the physical environment and the chemical makeup of the fluids that bathe the cells.
At the same time, the model does not include all the other cell types and immune interactions found in a living body. Those missing players could be crucial for understanding how whole diets, like a ketogenic diet, influence cancer in patients.
The work also underscores how complex and individualized cancer can be.
“Every tumor is an individual’s tumor,” added Nelson. “How do you know when you have enough different tumor models to represent the patient population? Maybe that’s not feasible.”
By striking a balance between oversimplified lab dishes and highly complex animal models, 3D microfluidic systems like the one used in this study offer a promising middle ground. They are controlled enough to tease apart specific factors — such as fat versus insulin — yet realistic enough to capture key aspects of tumor behavior.
For example, previous research has shown that ketogenic diets can delay tumor growth in some settings. The new findings suggest that this effect may not come from directly starving tumor cells in the way many people imagine. Instead, it might be mediated through other parts of the tumor environment, such as immune cells or blood vessels, which were not present in the Princeton model.
That kind of insight can help researchers narrow down where to look next for new treatments and prevention strategies. If dietary fat pushes tumors toward a more invasive state by changing their structure and gene activity, then drugs that interfere with those specific pathways — or lifestyle interventions that reduce harmful fat exposure — could become part of a more personalized approach to care.
The paper, titled “Fat promotes growth and invasion in a 3D microfluidic tumor model of triple-negative breast cancer,” was authored by an interdisciplinary team spanning bioengineering, chemistry and genomics. Their work adds an important piece to the puzzle of how what we eat can influence how cancers grow and spread.
For patients and clinicians, the study does not offer immediate diet prescriptions, but it does strengthen the case that nutrition and tumor biology are deeply connected. As more research builds on these findings, the hope is that understanding those connections will lead to better ways to prevent aggressive disease and to tailor treatments to each person’s unique cancer.
Source: Princeton Engineering