Tight junction-high and CDH17-positive cell population is the source of colorectal cancer liver metastases

Abstract

Colorectal cancer (CRC) frequently develops aggressive metastatic disease, yet the cellular features that enable dissemination remain poorly defined. IKK alpha, a kinase traditionally linked to stress and inflammatory signaling, is increasingly recognized for broader functions in cancer. Here, we show that loss of IKK alpha unexpectedly promotes metastasis in CRC. Using patient-derived organoids, we find that genetic or pharmacological inhibition of IKK alpha stabilizes tight-junction components, leading to the emergence of compact epithelial clusters with a heightened ability to spread and colonize the liver. Single-cell transcriptomics reveals expansion of a CDH17(+)/CLDN2(+) epithelial subpopulation that dominates metastatic lesions, a finding validated by tissue staining. Remarkably, disrupting CLDN2 completely eliminates the metastatic advantage caused by IKK alpha loss. These results identify a metastasis-competent epithelial state driven by tight-junction remodeling and uncover a vulnerable node that may be exploited therapeutically in aggressive colorectal cancer.