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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月3日

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  • Daniel Alvarez-Villanueva,
  • María Maqueda,
  • Dina Harti,
  • Eric Canton,
  • Evelyn Andrades,
  • Joan Bertran,
  • María Martínez-Iniesta,
  • Laura Solé,
  • Violeta García-Hernández,
  • Ángela Montoto,
  • Teresa Lobo-Jarne,
  • Josune Alonso-Marañón,
  • Patricia Herrero-Molinero,
  • Mónica Larrubia-Loring,
  • Anna Tramuns,
  • Kieran Wynne,
  • Indrani Bera,
  • David Matallanas,
  • Alberto Villanueva,
  • Anna Bigas,
  • Mar Iglesias,
  • Lluís Espinosa

摘要

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.