Abstract
BACKGROUND: Liver metastasis accounts for most deaths in colorectal cancer patients, but we still lack a clear understanding of how this devastating process unfolds at the molecular level. Identifying these mechanisms could lead to better ways to predict and treat metastatic disease. METHODS: We performed proteomic analysis on 38 tissue samples, including benign adenomas, primary colorectal tumors, and liver metastases, to map the molecular changes that drive cancer spread to the liver. RESULTS: We found striking differences in protein expression patterns across tissue types. Primary tumors showed massive protein changes compared to normal tissue (nearly 1,900 alterations), but liver metastases were surprisingly selective in their modifications (just 89 unique changes from primary tumors). This specificity indicates that liver colonization depends on precise molecular adjustments rather than random cellular disruption. The proteins involved in metastasis fell into three main categories: tissue restructuring to support tumor growth, mechanisms to avoid immune detection, and blood clotting factors that help cancer cells establish themselves in the liver. We validated three biomarkers with clinical potential: HDHD3 shows promise for detecting existing metastases, while OLFM4 and ZNF34 can help identify primary tumors at high risk for spreading. CONCLUSIONS: Our work reveals that colorectal cancer liver metastasis involves targeted molecular changes rather than widespread cellular chaos. The biomarkers we identified could improve early detection of metastatic risk and guide more personalized treatment decisions for patients.