Inhibition of Ephrin B2 Reverse Signaling Abolishes Multiple Myeloma Pathogenesis.
Publication Year:
2024
PubMed ID:
38231476
Funding Grants:
Public Summary:
Researchers studied how the cells that line blood vessels in the bone marrow (called endothelial cells) help the blood cancer multiple myeloma grow and resist treatment.
They discovered that these endothelial cells and the myeloma cells “talk” to each other using a set of proteins—specifically, EPHB1 and EPHB4 on the endothelial cells and ephrin B2 (EFNB2) on the myeloma cells. This communication helps the cancer survive, spread, and resist chemotherapy.
When the researchers blocked or removed any part of this signaling system (either EPHB1/EPHB4 in endothelial cells or EFNB2 in the myeloma cells), the cancer cells:
• Stopped multiplying,
• Were unable to grow in mice, and
• Became more sensitive to chemotherapy.
They also tested a drug-like molecule designed to target EFNB2, and it successfully slowed myeloma growth in mice.
In contrast, when the cancer cells made extra EFNB2, they became stronger, more resistant to treatment, and activated survival pathways inside the cell. A mutant form of EFNB2 that couldn’t send signals had the opposite effect—it made the cancer cells weaker and easier to kill.
Finally, data from patients showed that people with higher EFNB2 levels tend to have more aggressive diseases and shorter survival times.
Scientific Abstract:
Bone marrow vascular endothelial cells (BM EC) regulate multiple myeloma pathogenesis. Identification of the mechanisms underlying this interaction could lead to the development of improved strategies for treating multiple myeloma. Here, we performed a transcriptomic analysis of human ECs with high capacity to promote multiple myeloma growth, revealing overexpression of the receptor tyrosine kinases, EPHB1 and EPHB4, in multiple myeloma-supportive ECs. Expression of ephrin B2 (EFNB2), the binding partner for EPHB1 and EPHB4, was significantly increased in multiple myeloma cells. Silencing EPHB1 or EPHB4 in ECs suppressed multiple myeloma growth in coculture. Similarly, loss of EFNB2 in multiple myeloma cells blocked multiple myeloma proliferation and survival in vitro, abrogated multiple myeloma engraftment in immune-deficient mice, and increased multiple myeloma sensitivity to chemotherapy. Administration of an EFNB2-targeted single-chain variable fragment also suppressed multiple myeloma growth in vivo. In contrast, overexpression of EFNB2 in multiple myeloma cells increased STAT5 activation, increased multiple myeloma cell survival and proliferation, and decreased multiple myeloma sensitivity to chemotherapy. Conversely, expression of mutant EFNB2 lacking reverse signaling capacity in multiple myeloma cells increased multiple myeloma cell death and sensitivity to chemotherapy and abolished multiple myeloma growth in vivo. Complementary analysis of multiple myeloma patient data revealed that increased EFNB2 expression is associated with adverse-risk disease and decreased survival. This study suggests that EFNB2 reverse signaling controls multiple myeloma pathogenesis and can be therapeutically targeted to improve multiple myeloma outcomes. SIGNIFICANCE: Ephrin B2 reverse signaling mediated by endothelial cells directly regulates multiple myeloma progression and treatment resistance, which can be overcome through targeted inhibition of ephrin B2 to abolish myeloma.