Disseminated tumor cell of colorectal cancer adopt the wound healing program of epidermal keratinocyte [RNA-seq]

Disseminated tumor cells (DTCs) are a critical cell population in the metastasis process, and understanding their features is essential for the development of cancer treatment. We show that DTCs of colorectal cancer (CRC) transiently adopted the cellular state resembling to the activated epidermal keratinocyte during wound healing. Using the orthotropic transplantation of patient derived organoids (PDOs), we demonstrated that collective migrating cell clusters in primary site did not contain cancer stem cells but contained cells expressing wound-inducible keratins. Mechanistically, inhibition of EZH2 methyltransferase and activation of YAP signaling synergistically promoted DTC phenotype and potentiated dissemination to the distant organs. Collectively, these observations demonstrated that CRC cells alter the cellular hierarchy and adopt re-epithelization program resembling to the tissue repair process to generate DTCs.