Tight junction-high and CDH17-positive cell population is the source of colorectal cancer liver metastases
Colorectal cancer (CRC) frequently develops aggressive metastatic disease, yet the cellular features that enable dissemination remain poorly defined. IKKα, a kinase traditionally linked to stress and inflammatory signaling, is increasingly recognized for broader functions in cancer. Here, we show that loss of IKKα unexpectedly promotes metastasis in CRC. Using patient-derived organoids, we find that genetic or pharmacological inhibition of IKKα 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 IKKα 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.
Authors
- Daniel Alvarez-Villanueva
- Patricia Herrero-Molinero
- Laura Solé (ORCID: https://orcid.org/0000-0002-3195-0565)
- María Maqueda (ORCID: https://orcid.org/0000-0001-9304-1714)
- Joan Bertran (ORCID: https://orcid.org/0000-0002-4276-336X)
- Indrani Bera (ORCID: https://orcid.org/0000-0003-4198-0204)
- David Matallanas (ORCID: https://orcid.org/0000-0002-2360-3141)
- Ángela Montoto (ORCID: https://orcid.org/0000-0002-1127-3632)
- Alberto Villanueva
- Lluis Espinosa
- Mónica Larrubia-Loring (ORCID: https://orcid.org/0009-0002-9054-9269)
- Eric Cantón
- Anna Bigas
- María Martínez-Iniesta
- Teresa Lobo-Jarne
- Anna Tramuns
- Mar Iglesias
- Evelyn Andrades
- Josune Alonso-Marañón
- Violeta García-Hernández
- Dina Harti
- Kieran Wynne
Institutions
- University College Dublin (IE)
- Universitat de Vic - Universitat Central de Catalunya (ES)
- Universitat Pompeu Fabra (ES)
- Bellvitge University Hospital (ES)
- Institut d'Investigació Biomédica de Bellvitge (ES)
- Josep Carreras Leukaemia Research Institute (ES)
- Institut Català d'Oncologia (ES)
- Hospital Del Mar (ES)
- Centro de Investigación Biomédica en Red de Cáncer (ES)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-01-03
- DOI
- https://doi.org/10.1038/s41467-025-68169-3
- Primary Topic
- Barrier Structure and Function Studies
- Type
- article
- Field-Weighted Citation Impact
- 0.00