Biology and preclinical models of colorectal cancer metastasis

Metastatic colorectal cancer (mCRC) is the principal cause of CRC-related mortality, yet the biology of mCRC remains only partly understood and challenging to interrogate experimentally. Despite recent progress in mapping recurrent genetic and epigenetic alterations and treatment responses of mCRC, these efforts provide limited insight into how heterogeneous primary tumors breach tissue barriers, survive in circulation, and colonize distant organs. In this review, we summarize current experimental systems for studying mCRC, including genetically engineered mouse models, carcinogen-induced and transplant models, and patient-derived organoid and xenograft platforms, and discuss how each captures or fails to capture key steps of the metastatic cascade and organ-specific microenvironments. We highlight practical obstacles to longitudinal sampling and quantitative readouts of metastatic burden, as well as conceptual gaps in modeling immune and stromal influences. Finally, we outline how emerging approaches, including single-cell and spatial transcriptomics, and advances in longitudinal tracking of metastatic burden could be combined into an integrated framework that more faithfully links mechanistic insight to clinical behavior and ultimately to metastasis-specific therapies.