Colorectal cancer metastases in fatty liver grow differently

Colorectal cancer metastases in fatty liver may grow not as clearly separated nodules, but by weaving themselves into the surrounding organ. This infiltrative pattern is associated with a poorer prognosis, and the new study explains how excess liver fat could help create the metabolic conditions that favour it.

When colorectal cancer cells reach the liver, their metastases do not all expand in the same way. Some become enclosed by a dense layer of connective tissue that separates the tumour from healthy liver. Others spread along the tumour edge, replace liver cells and co-opt the organ’s existing blood vessels. This second, “replacement” growth pattern is harder to control and is linked to more aggressive disease.

The distinction matters clinically. The authors note that five-year overall survival is below 44.2% for patients with replacement metastases, compared with 73.4% for those with encapsulated metastases. What has remained unclear is why one growth pattern develops in some patients and another pattern in others.

The liver is not a passive background

The researchers examined colorectal cancer liver metastases from treatment-naive patients and compared their growth patterns with the presence of hepatic steatosis, the accumulation of fat in liver cells. Replacement metastases occurred more often in patients with steatosis than in those without it.

That patient-level finding establishes an association, not causation. The team therefore tested the proposed mechanism in cancer cells, patient-derived organoids, mouse models and patient-derived xenografts. Across these systems, the results converged on the same metabolic pathway.

In a fatty liver environment, tumour cells increased fatty-acid oxidation. This promoted acetylation and stabilization of MYC, a major regulator of cancer-cell growth and metabolism. Proteins such as MYC are normally kept under control partly through degradation. When MYC became more stable, it remained active for longer and reprogrammed how the tumour cells used nutrients.

From fatty acids to collagen

Stabilized MYC increased the production of proline. This amino acid is an essential building block of collagen, the strong structural protein that helps organize the extracellular matrix around cells. Greater proline and collagen synthesis supported an environment in which tumour cells could spread through liver tissue and grow in the replacement pattern.

Spatial analyses of metabolites and proteins in human metastases supported this mechanism. Replacement lesions showed evidence of increased proline metabolism and collagen production at the interface where tumour cells met the liver.

The researchers then disrupted different steps in the pathway. Targeting MYC, the proline-synthesis enzyme P5CS or the collagen component COL1A1 reduced the formation and growth of replacement metastases in organoids, mice and models carrying patient-derived tumour tissue. An experimental MYC inhibitor also showed stronger activity against replacement metastases than against encapsulated lesions.

The authors also performed a small retrospective analysis of nine participants in the phase I trial of the MYC inhibitor OMO-103 who had different metastatic solid tumours. Higher liver fat was associated with a more favourable change in tumour burden after nine weeks. This was an exploratory signal only: the group was very small, included several cancer types and had not been assembled to validate liver fat as a biomarker.

These findings do not amount to a new treatment for patients. The study was primarily mechanistic and preclinical. It did not establish that inhibiting this pathway improves survival in humans or that the interventions can be used safely in routine care. Nor does it show that treating fatty liver will prevent metastasis or reverse a growth pattern that has already formed.

The study assessed fat accumulation in the liver, not the effects of a particular diet, obesity intervention or treatment for fatty liver disease. Steatosis can arise in different metabolic settings. The results therefore cannot be used to conclude that dietary change alone will alter the behaviour of established metastases.

The broader conclusion extends beyond any single protein or drug target. A metastasis depends not only on the genetic and molecular properties of the cancer cell, but also on the physiological state of the organ it enters. Fat accumulation can alter the nutrients available in the liver and steer tumour cells toward a more aggressive mode of growth. In future clinical trials, measuring liver fat and identifying metastatic growth patterns could help select patients more precisely, but that possibility still requires prospective validation.