Consensus molecular subtyping of colorectal carcinoma brain metastases reveals a metabolic signature associated with poor patient survival.

The transcriptomic classification of primary colorectal cancer (CRC) into distinct consensus molecular subtypes (CMSs) is a well-described strategy for patient stratification. However, the molecular nature of CRC metastases remains poorly investigated. To this end, this study aimed to identify and compare organotropic CMS frequencies in CRC liver and brain metastases. Compared to reported CMS frequencies in primary CRC, liver metastases from CRC patients were CMS4-enriched and CMS3-depleted, whereas brain metastases mainly clustered as CMS3 and rarely as CMS4. Regarding overall survival rates, CMS4 was the most favorable subtype for patients with hepatic lesions, followed by CMS1 and CMS2. The survival of patients with brain metastases did not correlate with CMS. However, we identified a CMS3-related metabolic gene signature, specifically upregulated in central nervous system (CNS)-infiltrating CRC, as a negative prognostic marker and potential tumor progressor. In summary, subtyping of CRC metastases revealed an organotropic CMS distribution in liver and brain with impact on patient survival. CNS-infiltrating CRC samples were enriched for CMS3 and predictive metabolic biomarkers, suggesting metabolic dysregulation of CRC cells as a prerequisite for metastatic colonization of the brain.