The Eph-Receptor A7 Is a Soluble Tumor Suppressor for Follicular Lymphoma

Insights into cancer genetics can lead to therapeutic opportunities. By cross-referencing chromosomal changes with an unbiased genetic screen we identify the ephrin receptor A7 ( EPHA7) as a tumor suppressor in follicular lymphoma (FL). EPHA7 is a target of 6q deletions and inactivated in 72% of FLs. Knockdown of EPHA7 drives lymphoma development in a murine FL model. In analogy to its physiological function in brain development, a soluble splice variant of EPHA7 (EPHA7 TR) interferes with another Eph-receptor and blocks oncogenic signals in lymphoma cells. Consistent with this drug-like activity, administration of the purified EPHA7 TR protein produces antitumor effects against xenografted human lymphomas. Further, by fusing EPHA7 TR to the anti-CD20 antibody (rituximab) we can directly target this tumor suppressor to lymphomas in vivo. Our study attests to the power of combining descriptive tumor genomics with functional screens and reveals EPHA7 TR as tumor suppressor with immediate therapeutic potential. [Display omitted] ► Cancer genomics and genetic screens are complementary tools in cancer gene discovery ► EPHA7 TR is a soluble tumor suppressor that is lost in ∼70% of follicular lymphomas ► EPHA7 TR blocks EPHA-receptor activation and ERK and SRC signals in lymphoma ► An anti-CD20-EPHA7 TR fusion antibody is a new therapeutic reagent against lymphoma A soluble splice variant of EPHA7 blocks oncogenic signals in lymphoma cells and exerts antitumor effects in vivo. Treatment with this soluble receptor, as well as an EPHA7-antibody fusion amelioriates disease in mouse models of lymphoma, presenting a therapeutic approach for this chemotherapy-refractive disease.