How Fatty Liver Makes Cancer More Aggressive: Scientists Uncover an Unexpected Link

Researchers from VIB and KU Leuven, together with international collaborators, have discovered that fatty liver disease may promote the development of the most aggressive form of metastatic colorectal cancer. The study, published in Nature, demonstrates that the body's metabolic state can directly influence tumor behavior and disease outcomes.

Colorectal cancer remains one of the leading causes of cancer-related death worldwide. It accounts for nearly one in every ten cancer cases and is the leading cause of cancer death among people under the age of 50. One of the greatest clinical challenges is the development of metastases—secondary tumors that most commonly spread to the liver and dramatically worsen prognosis. Up to half of all patients develop liver metastases.

Scientists distinguish between two major types of liver metastases. In so-called encapsulated metastases, the tumor remains separated from healthy liver tissue, and the five-year survival rate reaches approximately 73%. In contrast, replacement metastases invade healthy liver tissue and integrate with its structure, making the disease far more aggressive and reducing five-year survival to below 44%.

Until now, little was known about why different patients develop these distinct metastatic patterns. The new study identifies fatty liver disease (hepatic steatosis) as an important risk factor. As obesity and metabolic disorders become increasingly common worldwide, fatty liver disease is also becoming more prevalent.

Analysis of patient samples and experimental models showed that fatty liver strongly favors the development of aggressive replacement-type liver metastases. According to the researchers, these findings reshape our understanding of the role of metabolic health in cancer progression.

The key mechanism involves metabolic changes within the liver. As fat accumulates, levels of fatty acids increase, affecting cancer cells by stabilizing MYC, one of the major proteins that drives tumor growth. Activated MYC enhances the synthesis of the amino acid proline, which is essential for collagen production. This, in turn, creates a structural scaffold that facilitates the invasion and spread of cancer cells throughout the liver.

These findings suggest that fatty liver disease is not merely a coexisting condition but actively creates an environment that makes liver metastases more aggressive and invasive.

The researchers note that the discovery also has important clinical implications. Drugs targeting MYC are already undergoing clinical trials, and the new findings could help identify patients who are most likely to benefit from these therapies—particularly individuals with fatty liver disease and aggressive replacement-type metastases.

The study also highlights several promising therapeutic strategies, including targeting MYC, blocking proline synthesis, or inhibiting collagen formation. In experimental models, these approaches reduced both metastatic growth and tumor spread.

The authors conclude that considering a patient's metabolic health could become an important component of personalized oncology. In the future, liver fat content may serve as a biomarker for predicting disease progression and guiding treatment decisions.

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