Researchers from VIB and the University of Leuven, in collaboration with international partners, have revealed how fatty liver disease drives the most aggressive form of metastatic colorectal cancer. Research results published in major journals natureIn addition to explaining why some patients face dramatically poor outcomes, we highlight that metabolic conditions such as fatty liver disease can directly influence cancer progression, paving the way for more precise treatments tailored to a patient’s metabolic health.
Colorectal cancer (CRC) remains one of the leading causes of cancer-related deaths worldwide, accounting for nearly 1 in 10 people diagnosed with cancer, and is now the leading cause of cancer-related deaths in people under 50 years of age. The main reason for these poor outcomes is that up to 50% of patients develop secondary tumors called metastases in distant organs (mainly the liver), which dramatically reduces survival rates.
The survival of patients who develop metastases to the liver is greatly influenced by how the tumor grows within the liver. Surprisingly, the 5-year survival rate for patients with metastases that remain separate from healthy liver tissue, so-called encapsulated metastases, can reach approximately 73%. In contrast, patients with displacement metastases, where cancer cells infiltrate and interact with healthy liver tissue, face more aggressive disease and have a reduced survival rate of less than 44%.
Despite this clear clinical distinction, our understanding of what drives the development of these aggressive metastases remains limited, there are no treatments that specifically target them, and there is a significant unmet need for patients with diseases with poor prognosis.
Common metabolic conditions with unexpected consequences
A new study led by the laboratory of Professor Sarah Maria Fendt (VIB-KU Leuven Center for Cancer Biology) has identified an important lifestyle-related factor that helps explain why some patients develop these high-risk metastases: the accumulation of fat in the liver, known as fatty liver or fatty liver.
By analyzing patient samples in parallel with an experimental model, researchers found that patients with fatty liver were significantly more likely to develop progressive displacement metastases. This is particularly important given that the prevalence of fatty liver disease is rapidly increasing worldwide due to increases in obesity and metabolic disorders.
This study shows that conditions that we usually think of as background metabolic problems can directly influence cancer behavior. This emphasizes that the patient’s physiology is not just a bystander but an active determinant of disease progression. ”
Professor Sarah-Maria Fendt, Senior Author, Leuven VIB-KU
How fat reshapes tumor biology
The study also uncovered a molecular mechanism linking fatty liver and the spread of aggressive cancers. In fatty liver, elevated fatty acid levels rewire cancer cell metabolism and behavior by stabilizing the protein MYC, a well-known driver of cancer growth. Stabilized MYC increases the production of proline, an amino acid that serves as a key component of collagen. This collagen creates a structural environment for tumor cells to infiltrate and expand within the liver, leading to displacement metastases.
“Simply put, fatty liver provides both the signals and building materials that tumors need to grow more aggressively,” Fendt explains. “It fundamentally changes the rules of how metastasis occurs.”
Immediate effects: Improving clinical trial success rates
One of the most direct and tangible impacts of this research is in improving how cancer patients are selected to participate in clinical trials. Drugs that target MYC are already being tested for safety in patients, but their clinical success will depend on identifying the patients most likely to benefit.
This study provides a potential solution by showing that these agents may be most effective in patients with fatty liver and displacement metastases and providing a clear strategy for patient selection.
“This gives us a powerful new way to stratify patients,” Fendt said. “By identifying patients who are most likely to benefit, we can conduct clinical trials more efficiently and ultimately bring effective treatments to patients more quickly.”
Improved patient selection could increase trial success rates, reduce unnecessary treatments, and accelerate the development of targeted therapies.
Opening new avenues for treatment
Importantly, this study shows that this process can be exploited. By targeting different steps in this pathway, including MYC protein, proline production, and collagen formation, researchers were able to significantly reduce the formation and growth of progressive metastases in sophisticated experimental systems, including patient-derived tissue models.
These findings present opportunities for new treatments tailored to patients’ metabolic status.
“Our results suggest that we can intervene at multiple levels of this process,” Fendt says. “This opens up entirely new possibilities to design treatments that specifically target the most dangerous forms of metastatic disease, especially in patients with liver diseases such as steatosis.”
Importantly, this study highlights the importance of incorporating metabolic health into cancer treatment. Liver fat content may serve as a biomarker to guide treatment decisions and predict disease progression.
“This study has changed our perspective,” says the study’s lead author, Dr. Yimin Peng Winkler (VIB-KU Leuven, Düsseldorf University Hospital). “This shows that to effectively treat cancer, we need to consider not only the tumor but also the environment on which it depends. Only then can we design truly precise and effective treatments.”
Broad changes in understanding of cancer
More broadly, this study highlights the fundamental principle that cancer progression is shaped not only by the tumor cells themselves, but also by the body’s environment. By revealing how fatty liver disease promotes malignant metastasis, this study provides both a mechanistic explanation for differences in patient outcomes and a roadmap to improve them.
As metabolic diseases continue to increase worldwide, these insights may become increasingly important not only for understanding cancer biology but also for changing the way patients are diagnosed, stratified, and treated in the future.
sauce:
Flemish Institute of Biotechnology
Reference magazines:
Penn Winkler, Y. others. (2026). Steatosis forms the heterogeneity of liver metastases that determines the prognosis in CRC. nature. DOI: 10.1038/s41586-026-10686-2. https://www.nature.com/articles/s41586-026-10686-2
