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Role of CD44 isoforms in epithelial-mesenchymal plasticity and metastasis

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Abstract

Cellular plasticity lies at the core of cancer progression, metastasis, and resistance to treatment. Stemness and epithelial-mesenchymal plasticity in cancer are concepts that represent a cancer cell’s ability to coopt and adapt normal developmental programs to promote survival and expansion. The cancer stem cell model states that a small subset of cancer cells with stem cell-like properties are responsible for driving tumorigenesis and metastasis while remaining especially resistant to common chemotherapeutic drugs. Epithelial-mesenchymal plasticity describes a cancer cell’s ability to transition between epithelial and mesenchymal phenotypes which drives invasion and metastasis. Recent research supports the existence of stable epithelial/mesenchymal hybrid phenotypes which represent highly plastic states with cancer stem cell characteristics. The cell adhesion molecule CD44 is a widely accepted marker for cancer stem cells, and it lies at a functional intersection between signaling networks regulating both stemness and epithelial-mesenchymal plasticity. CD44 expression is complex, with alternative splicing producing many isoforms. Interestingly, not only does the pattern of isoform expression change during transitions between epithelial and mesenchymal phenotypes in cancer, but these isoforms have distinct effects on cell behavior including the promotion of metastasis and stemness. The role of CD44 both downstream and upstream of signaling pathways regulating epithelial-mesenchymal plasticity and stemness make this protein a valuable target for further research and therapeutic intervention.

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Acknowledgements

This study was supported by BX002086 (VA merit), CA250383 (NIH/NCI), CA216746 (NIH/NCI) and Nebraska Research Initiative (NRI) to P.D.

Funding

This study was supported by BX002086 (VA merit), CA250383 (NIH/NCI), CA216746 (NIH/NCI) and Nebraska Research Initiative (NRI) to P.D.

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Authors and Affiliations

  1. VA Nebraska-Western Iowa Health Care System, Omaha, NE, USA

    Punita Dhawan

  2. Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA

    Mark Primeaux, Saiprasad Gowrikumar & Punita Dhawan

  3. Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA

    Punita Dhawan

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  1. Mark Primeaux
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PD and MP: Conceptualization, PD, MP, SG: Writing, Review, and Editing, PD: Supervision, PD: Funding Acquisition. The author(s) read and approved the final manuscript.

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Primeaux, M., Gowrikumar, S. & Dhawan, P. Role of CD44 isoforms in epithelial-mesenchymal plasticity and metastasis. Clin Exp Metastasis 39, 391–406 (2022). https://doi.org/10.1007/s10585-022-10146-x

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