Multilevel Heterogeneity of Colorectal Cancer Liver Metastasis

Simple Summary Liver metastasis remains a major hurdle to the long-lasting survival of patients with colorectal cancer (CRC). When CRC spreads to the liver, tumor cells undergo a series of changes to adapt to the new environment, leading to evident heterogeneity. Therefore, understanding the features of metastatic tumor cells in the liver is valuable for the overall control of patients with colorectal cancer liver metastasis (CRLM). In this review, we provide a comprehensive overview of the spatial heterogeneity of CRLM at different molecular levels, including genetics, transcriptomics, proteomics, metabolism, and immune levels. While genetic heterogeneity may not be apparent, the other four levels demonstrate significant heterogeneity. Compared to primary CRC, the epithelial-mesenchymal transition (EMT)-related proteins are significantly altered. Moreover, the metabolic activity is enhanced and the infiltration of immuno-suppressive cells is increased in CRLM. All these changes promote the metastasis and colonization of CRC cells. Based on these findings, we also summarize preclinical therapeutic modalities targeting the heterogeneity of CRLM, aiming to provide new directions for clinical interventions and improve the survival rates of these patients.Abstract Colorectal cancer liver metastasis (CRLM) is a highly heterogeneous disease. Therapies that target both primary foci and liver metastasis are severely lacking. Therefore, understanding the features of metastatic tumor cells in the liver is valuable for the overall control of CRLM patients. In this review, we summarize the heterogeneity exhibited in CRLM from five aspects (gene, transcriptome, protein, metabolism, and immunity). In addition to genetic heterogeneity, the other four aspects exhibit significant heterogeneity. Compared to primary CRC, the dysregulation of epithelial-mesenchymal transition (EMT)-related proteins, the enhanced metabolic activity, and the increased infiltration of immunosuppressive cells are detected in CRLM. Preclinical evidence shows that targeting the EMT process or enhancing cellular metabolism may represent a novel approach to increasing the therapeutic efficacy of CRLM.