The membrane-cytoskeleton linker ezrin is necessary for osteosarcoma metastasis

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 cancer. 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 membrane. 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.

Development and external validation of nomograms predicting distant metastases and overall survival after neoadjuvant chemotherapy and surgery for patients with nonmetastatic osteosarcoma: A multi‐institutional study

“…Therefore, considering the nature of this multi‐institutional study, we felt it necessary to omit the data for ALP and LDH. However, it is likely that the inclusion of these serological markers or known molecular markers such as P‐glycoprotein,31 CXCR4,32 and ezrin33 would improve the predictive ability of future nomograms. Fifth, the trunk cases had better outcomes than expected (better than proximal humerus cases) with respect to MFS.…”

Phosphorylated ezrin is located in the nucleus of the osteosarcoma cell

“…20 In a mouse model of osteosarcoma, ezrin was necessary for metastasis, and in dog tumors, a high expression of ezrin was associated with the early development of metastasis. 8 A relationship was also shown between high expressions of ezrin and poor outcome in 19 pediatric osteosarcoma patients. 8 More importantly, using dominant-negative mutants, antisense RNA or RNA interference, both groups demonstrated that ezrin overexpression is not only sufficient for metastatic progression, but it is also necessary, at least in these experimental systems.…”

“…6,7 The identification of ezrin expression is a necessary component in osteosarcoma metastasis and it makes the study of this protein crucial in understanding the molecular pathways involved in metastatic diffusion. 8 Ezrin, the product of the Vil2 gene, is present in the cytoplasm in an inactive form but after threonine and tyrosine phosphorylation, ezrin assumes an active form, moving to the cell membrane and tethering F-actin to the cell membrane. 9 Ezrin has been associated with the formation of specialized cell surface domains and assists in the placement of molecules within these structures.…”

Inhibition of the hyaluronan-CD44 interaction by merlin contributes to the tumor-suppressor activity of merlin

“…CD44 and ezrin play important roles in promoting tumor metastasis (Yu et al, 1997;Stamenkovic 1999, 2000;Yu et al, 2004;Khanna et al, 2001Khanna et al, , 2004, whereas merlin acts as a tumor suppressor (Rouleau et al, 1993;Trofatter et al, 1993;Lutchman and Rouleau, 1995;Sherman et al, 1997;McClatchey et al, 1998;Giovannini et al, 1999Giovannini et al, , 2000. Thus far, the functional relationship between CD44 and merlin and the manner in which CD44 affects the tumor-suppressing activity of merlin have not been established.…”