Claudin-1 interacts with EPHA2 to promote cancer stemness and chemoresistance in colorectal cancer

Mark Primeaux, Xiangdong Liu, Saiprasad Gowrikumar, Iram Fatima, Kurt W. Fisher, Dhundy Bastola, Alex J. Vecchio, Amar B. Singh, Punita Dhawan

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


Therapy resistance is the primary problem in treating late-stage colorectal cancer (CRC). Claudins are frequently dysregulated in cancer, and several are being investigated as novel therapeutic targets and biomarkers. We have previously demonstrated that Claudin-1 (CLDN1) expression in CRC promotes epithelial-mesenchymal transition, metastasis, and resistance to anoikis. Here, we hypothesize that CLDN1 promotes cancer stemness and chemoresistance in CRC. We found that high CLDN1 expression in CRC is associated with cancer stemness and chemoresistance signaling pathways in patient datasets, and it promotes chemoresistance both in vitro and in vivo. Using functional stemness assays, proteomics, biophysical binding assays, and patient-derived organoids, we found that CLDN1 promotes properties of cancer stemness including CD44 expression, tumor-initiating potential, and chemoresistance through a direct interaction with ephrin type-A receptor 2 (EPHA2) tyrosine kinase. This interaction is dependent on the CLDN1 PDZ-binding motif, increases EPHA2 protein expression by inhibiting its degradation, and enhances downstream AKT signaling and CD44 expression to promote stemness and chemoresistance. These results suggest CLDN1 is a viable target for pharmacological intervention and/or biomarker development.

Original languageEnglish (US)
Article number216479
JournalCancer Letters
StatePublished - Nov 28 2023


  • Cancer stemness
  • Chemoresistance
  • Claudin-1
  • Colorectal cancer
  • EPHA2

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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