Abstract
EPHA3 is upregulated in mesenchymal GBM and maintains undifferentiated tumor-initiating cells.
Major finding: EPHA3 is upregulated in mesenchymal GBM and maintains undifferentiated tumor-initiating cells.
Mechanism: EPHA3 restricts differentiation by blocking MAPK signaling independent of its kinase activity.
Impact: A radiolabeled EPHA3-targeted monoclonal antibody induces sustained inhibition of tumor growth.
Less differentiated stem and progenitor cells contribute to tumor initiation and are thought to mediate recurrence of therapy-resistant tumors in such solid cancers as glioblastoma multiforme (GBM), emphasizing the need to identify strategies to target this cell population. EPH receptors and their ephrin ligands have been implicated in development and epithelial–mesenchymal transition and are aberrantly expressed in such cancers as GBM, but the role of specific EPH family members in tumorigenesis is unknown. Day and colleagues found that EPHA3 was frequently overexpressed in human GBM samples, particularly in the aggressive, undifferentiated mesenchymal subtype, compared with normal brain tissue. EPHA3 was coexpressed with markers of stem-like cells, including integrin α6, in patient tumors and was highly expressed in primary cultures enriched for tumor-initiating cells but not in differentiated cultures, suggesting that this receptor may restrict tumor cell differentiation. Consistent with this idea, EPHA3 depletion in undifferentiated GBM cells reduced proliferation and tumorsphere formation and enhanced expression of differentiation markers. EPHA3-dependent regulation of differentiation was mediated by suppression of mitogen-activated protein kinase (MAPK) signaling and was independent of EPHA3 kinase activity, as its basal activation and ligand expression were low in GBM cultures and tumor samples. Strikingly, knockdown of EPHA3 or depletion of EPHA3-expressing cells abrogated tumor formation and prolonged survival in both subcutaneous and intracranial xenograft models. In addition, only patient-derived tumor cells expressing high levels of EPHA3 formed tumors in mice, indicating that EPHA3 is necessary to maintain tumor-initiating potential. Furthermore, treatment with a radiolabeled EPHA3-targeted monoclonal antibody triggered tumor cell death in vitro and induced sustained tumor regression without toxicity in mice. These results identify EPHA3 as a critical regulator of dedifferentiated tumorigenic cells and suggest that it may be an effective, tumor-specific therapeutic target in GBM.
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