SRP493689 PRJNA1084820 GSE261012 Single-cell gene expression profiles of cells from colorectal cancer and chemically induced PDOs [scRNA-Seq] Phenotypic plasticity is a major driver of cancer progression, metastasis, and treatment resistance. However, the principles governing human cancer plasticity associated with poor prognosis remain poorly understood due to the lack of in vitro models. Here we identified a unique cancer cell state at single-cell resolution to predict poor prognosis across several human cancers with different clinical features, especially colorectal cancer (CRC) progression and metastasis, named the poor prognostic plastic state (PPPS). A functional patient-derived organoid xenograft (PDOX) model was developed to capture and maintain the PPPS in CRC. With a marker gene of MSLN (encoding mesothelin), this model was used to validate the role of the PPPS in promoting CRC metastasis. Moreover, precise manipulation of human cancer plasticity through the PPPS allows us to identify small-molecule inhibitors of non-canonical IKKs to promote malignancy, with clinical implications for targeting the PPPS to prevent CRC progression and metastasis. Overall design: Cells in primary tumor, current PDO and CiPDO of the same patient P18 were used for scRNA-seq analysis. CiPDOs of P7 cultured with and without WS6 were used for comparing the effect of WS6 treatment. GSE261012