Single-cell gene expression profiles of cells from colorectal cancer and chemically induced PDOs [scRNA-Seq]
Phenotypic plasticity is a hallmark feature driving cancer progression, metastasis, and therapy resistance. Fetal-like transcriptional programs have been increasingly implicated in promoting plastic cell states, yet their roles remain difficult to study due to limitations of existing culture models. Here, we establish a chemically defined patient-derived organoid (PDO) system that enables long-term expansion of colorectal cancer (CRC) cells while preserving fetal-like features associated with phenotypic plasticity. Using this model, we identify an oncofetal-like state (OnFS) that is enriched in advanced tumors and linked to key features of plasticity, including epithelial-mesenchymal plasticity, as well as increased metastasis and treatment resistance. Mechanistically, we show that FGF2–AP-1 signaling maintains the OnFS program and associated phenotypic plasticity in CRC. This model offers a powerful platform for studying the fetal-like features underlying cancer cell plasticity and their role in tumor progression and treatment resistance in CRC. Overall design: Cells in primary tumor, conventional PDO and CiPDO of the same patient P18 were used for scRNA-seq analysis.