Liver cancer risk: Researchers at MIT have discovered how high-fat diets transform liver cells in ways that increase cancer risk, offering new insights into one of the leading causes of liver tumours.
The study found that mature liver cells, called hepatocytes, revert to an immature, stem-cell-like condition when exposed to high-fat diets. While this change helps cells endure stressful environments in the short term, it makes them far more vulnerable to cancer over time.
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“If cells are forced to deal with a stressor, such as a high-fat diet, over and over again, they will do things that will help them survive, but at the risk of increased susceptibility to tumorigenesis,” said Alex K. Shalek, director of the Institute for Medical Engineering and Sciences at MIT and a member of the Koch Institute for Integrative Cancer Research.
The research team also pinpointed several regulatory proteins that control this cellular transformation. These proteins could serve as targets for medications designed to prevent tumour formation in patients at high risk.
Shalek led the study alongside Ömer Yilmaz, an associate professor of biology at MIT, and Wolfram Goessling, co-director of the Harvard-MIT Program in Health Sciences and Technology. The findings appear in the journal Cell.
High-fat diets can trigger inflammation and fat accumulation in the liver, a condition called steatotic liver disease. Long-term metabolic stress from factors like excessive alcohol use can also cause this disease, which may progress to cirrhosis, liver failure and cancer.
Scientists fed mice high-fat diets and used single-cell RNA sequencing to track gene activity in liver cells at multiple stages as disease developed. This technique allowed them to observe genetic changes as mice progressed from liver inflammation through tissue scarring to cancer.
During early disease stages, hepatocytes activated genes that enhanced their survival in hostile conditions. These included genes that made cells resistant to programmed death and more likely to multiply.
Simultaneously, cells deactivated genes essential for normal liver function, including those producing metabolic enzymes and secreted proteins.
Some changes occurred immediately, while others, like declining enzyme production, shifted gradually. Nearly all mice on high-fat diets developed liver cancer by the study’s end. Cells in immature states appear more prone to becoming cancerous if mutations occur later, researchers said.
“These cells have already turned on the same genes that they’re going to need to become cancerous. They’ve already shifted away from the mature identity that would otherwise drag down their ability to proliferate,” Tzouanas said. “Once a cell picks up the wrong mutation, then it’s really off to the races and they’ve already gotten a head start on some of those hallmarks of cancer.”
Scientists identified several genes that appear to orchestrate the reversion to immature states. One drug targeting thyroid hormone receptors recently won approval to treat MASH fibrosis, a severe form of steatotic liver disease. Another medication activating the enzyme HMGCS2 is now in clinical trials for the same condition.
The study also revealed SOX4, a regulatory protein normally active only during fetal development and in limited adult tissues but not the liver, as another potential treatment target.
Researchers analysed tissue samples from human patients at various disease stages, including those with liver disease who had not developed cancer. The analysis showed similar patterns to mouse studies: genes supporting normal liver function declined over time, while genes linked to immature states increased.
Gene expression patterns accurately predicted patient survival. Those with higher expression of cell-survival genes activated by high-fat diets lived shorter periods after tumours appeared. Patients with lower expression of genes supporting normal liver functions also had reduced survival times.
The team plans to investigate whether dietary changes or weight-loss medications like GLP-1 agonists can reverse alterations caused by high-fat diets. They also aim to study whether identified regulatory proteins could work as drug targets to prevent diseased liver tissue from turning cancerous.
Funding came from the Fannie and John Hertz Foundation, the National Science Foundation, the National Institutes of Health and the MIT Stem Cell Initiative.