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The membrane-cytoskeleton linker ezrin is necessary for osteosarcoma metastasis

Nature Medicine volume 10, pages 182–186 (2004)Cite this article

Abstract

Metastatic cancers, once established, are the primary cause of mortality associated with cancer. Previously, we used a genomic approach to identify metastasis-associated genes in cancer1. From this genomic data, we selected ezrin for further study based on its role in physically and functionally connecting the actin cytoskeleton to the cell membrane2. In a mouse model of osteosarcoma, a highly metastatic pediatric cancer, we found ezrin to be necessary for metastasis. By imaging metastatic cells in the lungs of mice, we showed that ezrin expression provided an early survival advantage for cancer cells that reached the lung. AKT and MAPK phosphorylation and activity were reduced when ezrin protein was suppressed. Ezrin-mediated early metastatic survival was partially dependent on activation of MAPK, but not AKT. To define the relevance of ezrin in the biology of metastasis, beyond the founding mouse model, we examined ezrin expression in dogs that naturally developed osteosarcoma. High ezrin expression in dog tumors was associated with early development of metastases. Consistent with this data, we found a significant association between high ezrin expression and poor outcome in pediatric osteosarcoma patients.

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Figure 1: Suppression of ezrin protein and disruption of ezrin function significantly reduced lung metastases in mice.
Figure 2: Suppression of ezrin protein resulted in decreased signaling and activity of AKT and p44/42 MAPK pathways in highly metastatic K7M2 osteosarcoma cells.
Figure 3: High primary tumor expression of ezrin was associated with significantly shortened DFI in pet dogs and pediatric patients with osteosarcoma.

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Acknowledgements

We thank P. Meltzer and J. Khan for useful discussions; B. Spinelli and K. Kelly for assistance with ezrin-T567A mutagenesis; the Pediatric Cooperative Human Tissue Network and Children's Oncology Group for contributions of tissue; and M. Devidas for collection of patient outcome data.

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Authors and Affiliations

  1. Pediatric Oncology Branch and Tissue Array Project Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Chand Khanna, Xiaolin Wan, Seuli Bose, Ryan Cassaday, Osarenoma Olomu, Arnulfo Mendoza, Choh Yeung & Lee J Helman

  2. Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Stephen M Hewitt

  3. Memorial Sloan Kettering Cancer Center, New York, 10021, New York, USA

    Richard Gorlick

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  1. Chand Khanna
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Correspondence to Chand Khanna.

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Khanna, C., Wan, X., Bose, S. et al. The membrane-cytoskeleton linker ezrin is necessary for osteosarcoma metastasis. Nat Med 10, 182–186 (2004). https://doi.org/10.1038/nm982

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