Colorectal cancer co-opts an epidermal wound healing program during metastasis to generate disseminated tumor cells

Abstract

Metastasis is the principal cause of death from colorectal cancer (CRC), yet the cellular states that enable tumor dissemination remain poorly defined. Disseminated tumor cells (DTCs) are rare, transient, and clinically inaccessible, limiting mechanistic insight into their biology. Here we show that CRC cells transiently adopt a wound-healing program normally used by epidermal keratinocytes during tissue repair to enable metastatic dissemination. Using serial orthotopic transplantation of patient-derived organoids to model metastasis, we find that DTCs lose cancer stem cell features and instead express wound-inducible keratins, including KRT17, before metastatic outgrowth. This state is reversible, as cells reacquire primary tumor–like characteristics upon colonization of distant organs. Mechanistically, this transition is associated with reduced EZH2 activity and activation of YAP signaling. Clinically, KRT17⁺ cells localize to the invasive front of primary CRCs and are absent from adjacent normal tissue. These findings uncover unexpected lineage plasticity across distinct developmental origins and identify a transient, targetable state critical for metastatic progression. The plasticity of disseminated tumor cells (DTCs) remains to be understood. Here the authors use serial orthotopic transplantation of colorectal patient-derived organoids to mimic cancer metastasis, and observe that DTCs have transiently adopted a wound-healing program of epidermal keratinocytes to express keratins before the metastatic outgrowth in distant organs.