Spatial Multi-Omics Landscape of Colorectal Cancer in the Context of Metastases

Colorectal cancer (CRC) metastases frequently recur due to minimal residual disease and persistent micrometastases after therapy. Here, we performed spatial multimodal profiling using spot-level and high-resolution spatial transcriptomics, multi-regional whole-genome sequencing following laser-capture microdissection, and high-plex protein imaging to map 49 tumors from 19 patients, encompassing paired primary CRC and matched liver (CLiM) and lung (CLuM) metastases. Phylogenetic reconstruction revealed that liver micrometastases (CLiMi) represent early clonal divergences that maintain a stem-like, quiescent phenotype consistent with metastatic dormancy. Spatially, we uncovered distinct stromal barriers: while macrometastases were encapsulated by myofibroblasts, micrometastases were surrounded by an immunosuppressive niche characterized by T-cell exhaustion and unique ligand-receptor signaling networks. Notably, we identified a CLiMi-specific six-gene signature that robustly predicts MRD status and disease-free survival across three independent cohorts. These findings elucidate the spatial evolution of CRC metastases and provide a tissue-based foundation for precision surveillance and therapeutic targeting.