Metastasis is the leading cause of colorectal cancer (CRC) mortality, yet metastatic lesions lack recurrent private driver mutations. Instead, genetic events in primary tumors may reprogram cellular states and enhance plasticity to facilitate dissemination. However, the underlying mechanisms and robust model systems required to interrogate these complex transitional processes are currently lacking.

We developed various highly metastatic CRC genetically engineered mouse models (GEMMs) representing classical and serrated CRC routes. To define mechanisms of plasticity, we developed a computational single-cell multiome compendium across GEMMs and fresh patient samples, integrating transcriptomic, proteomics, genomic and chromatin accessibility profiles to define cell states with metastatic competence. We further developed morphologic heterotypic tumor- and metastasis-derived organoids for functional and mechanistic perturbations.

Integrative genotype-phenotype mapping across 20 GEMMs identified a quantitatively expanded epithelial population with high transcriptional entropy driven by Fbxw7-mutation. This highly plastic population formed a central hub within the epithelial state network. Functionally, Fbxw7-loss massively enhanced metastatic propensity in GEMMs of serrated (90% vs. 25%) and classical (50% vs. 13%) CRC routes and reduced survival. Trajectory analyses demonstrated that cancer cells span a reversible continuum of transitional states, with a fixed mesenchymal endpoint, confirming FBXW7's role as a genetic driver of plasticity-driven metastasis. Our organoid platform faithfully recapitulated this continuum: cystic organoids retained high plasticity and metastatic competence, whereas branching organoids represented a phenotypically fixed, less metastatic endpoint. Mechanistically, we identified oncogenic signaling driven by Fbxw7-loss and the TGF-β co-receptor CD109 as a direct TGF-β target that enforces phenotypic stabilization. Importantly, CD109 expression marked the branching, locked state; its genetic deletion in GEMMs enhanced TGF-β responsiveness, shifted organoids toward the high-plasticity cystic state, and enhanced metastasis significantly. These findings establish CD109 as a molecular brake restraining plasticity within the continuum.

Here we show that the loss of the tumor suppressor Fbxw7 activates oncogenic signaling to unleash an epithelial state continuum fueling metastatic progression and therapy resistance. Metastasis arises from a reversible high-plasticity state, while phenotypic locking constrains dissemination. We demonstrate for the first time that genetically instructed plasticity is a critical driver of metastasis and provide the mechanistic framework to dissect and target plasticity-driven cancer progression.