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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/219676
IKKα modulates metastatic activity by preventing Tight Junctions stabilization and collective cell migration
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[eng] The IKKα kinase was previously found to activate multiple oncogenic and therapy-resistance pathways, including ATM/DDR, BRD4, and JAK/STAT3, independently of canonical NF-KB signaling. Here, we show that suppression of IKKα, either genetically or pharmacologically, imposes a pro- metastatic activity on colorectal cancer (CRC) patient-derived organoid (PDO) cells, which is linked to an increase in the protein levels of the tight junction protein ZO-1 and CLDN2, and a shift in their migratory mode towards collective migration. Analysis of single-cell (sc)RNAseq data revealed an accumulation of the tight junction signature in the metastatic populations. Specifically, PDO cells contain three distinct epithelial cell clusters (C2, C4 and C8) with concomitant enrichment of the tight junction and metastasis-associated EpiHR signatures, whose unique genetic signatures are upregulated upon depletion of IKKand enriched in PDO-derived metastases. CLDN2 inhibition or depletion abolishes the metastatic activity of IKKα KO PDO cells in vivo. By analyzing human paraffin- embedded CRC specimens, we have detected the presence of vascular tumor infiltrates with cluster- like or glandular phenotypes and high levels of ZO-1 and CLDN2-positive junctions. Collectively, our results suggest that high levels of tight junction proteins in CRC cells imposes a pro- metastatic collective CRC cell migration, which can be detected in the vascular infiltrates at diagnosis. We propose that after validation, this type of exploration could be standardized in the clinical routine.
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ALVAREZ VILLANUEVA, Daniel. IKKα modulates metastatic activity by preventing Tight Junctions stabilization and collective cell migration. [consulta: 10 de desembre de 2025]. [Disponible a: https://hdl.handle.net/2445/219676]