Our diet has a significant impact on plasma by influencing the levels of small molecules circulating therein. The same influence takes place in interstitial fluid. This alters the biochemical composition of the tumor microenvironment (TME), as these circulating nutrients are associated with tumor growth and its response to treatment. However, their direct response to the cancer cells remains obscure.
The Princeton team’s new study combined a 3D microfluidic tumor model with physiologically relevant culture media to determine the impact of circulating nutrient concentrations on tumor growth, cancer cell invasion, and overall tumor metabolism.
The findings revealed a shocking truth: High-fat diets are linked to aggressive breast cancer. More importantly, high-fat diets worsen the outcomes for cancer patients.
“That’s where the name cancer comes from, crab-like,” said Celeste Nelson, the study’s principal investigator and the Wilke Family Professor in Bioengineering and a professor of chemical and biological engineering. “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.”
The team used human plasma-like media (HPLM) and added insulin, glucose, ketones, or fat to mimic circulating nutrients characteristic of five dietary conditions: normal, after eating, diabetic, ketogenic, and high-fat.
In 2D culture, breast cancer cells (MDA-MB-231, triple-negative) were grown. In this condition, cells looked and grew about the same. But RNA sequencing showed that in high-fat conditions, genes linked to cell movement and tissue remodeling were more active. These changes also correlated with higher metabolic activity, even though the overall mix of secreted metabolites was largely similar across conditions.
Researchers then cultured cancer cells as 3D tumor-like aggregates (“tumors”) in a microfluidic system that generated interstitial fluid flow comparable to that observed in vivo. Little difference was observed across the four diets: from the baseline, the tumors remained relatively compact. But when fed fatty acids and cholesterol, they began forming small, hollow extensions that reached outward, a behavior typical of aggressive cancers.
There was also higher activity of the MMP1 gene, which helps break down collagen. This increase was strongly associated with the structural changes observed in the tumors.
Nelson said the MMP1 numbers leaped out in the data.
A high-fat diet plays an important role in increased gene expression. It degrades the surrounding environment, promoting the tumor’s aggression. However, this mechanism has not yet been proven. In the future, scientists may observe the influence of high-fat diets on tumor growth if MMP1 activity is inhibited.
One unexpected result was that tumors given nutrients to mimic a ketogenic diet (high fat, low carbs) did not look healthier than the baseline. The findings were limited, but they suggest the diet didn’t provide clear benefits in this model.
“We were expecting a ketogenic diet to be protective,” Nelson said. “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.”
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Even though this model was closer to real human environments than typical lab setups, the tumors studied were still simplified versions that left out many complex interactions found in the body. Nelson noted it may also be that tumors are simply too diverse to capture fully in a single study.
“Every tumor is an individual’s tumor,” Nelson said. “How do you know when you have enough different tumor models to represent the patient population? Maybe that’s not feasible.”
Beyond the main results, this study offers a more advanced approach to tumor growth than traditional methods.
The researchers said this system is especially good at sorting out causes behind observed effects. For example, while ketogenic diets have been shown to slow tumor growth, this study suggests the effect may come from changes in the tumor’s environment rather than the diet itself. That kind of process of elimination can highlight valuable new targets for future research.
Journal Reference:
- Maryam Kohram, Carolina Trenado-Yuste, Molly C. Brennan-Smith, Evelyn S. Navarro Salazar, Pengfei Zhang, Jasmine E. Hao, Xincheng Xu, Bharvi Chavre, William Oh, Sherry X. Zhang, Susan E. Leggett, Rolf-Peter Ryseck, Joshua D. Rabinowitz, and Celeste M. Nelson. Fat promotes growth and invasion in a 3D microfluidic tumor model of triple-negative breast cancer. APL Bioengineering. DOI: 10.1063/5.0291646