Breaking a vicious cycle in multiple myeloma

Multiple myeloma is a malignant disease of antibody producing plasma cells. As this devastating type of cancer locates to the bones it seems that multiple myeloma highly depends on close interactions with the bone marrow microenvironment. In our new paper by clinician-scientist Dr. Antonio Solimando et al. we describe our new discovery that multiple myeloma cells use an adhesion molecule called JAM-A (Junctional-adhesion-molecule A) to interact with blood vessel lining endothelial cells. It appears as these endothelial-multiple myeloma interactions feed into a vicious cycle propagating disease progression.

Our projected started with our initial observation that the expression level of JAM-A by malignant plasma cells can predict disease outcome. Subsequently, we discovered that elevated membrane expression of JAM-A also on bone marrow endothelial cells of patients with newly diagnosed or relapsed-refractory multiple myeloma cells predicted poor clinical outcome.

Based on this finding we investigated how elevated JAM-A levels would contribute to more aggressive disease. We discovered that direct contact of endothelial cells with multiple myeloma cells would enhance JAM-A levels. Then it got even more interesting, as the cell adhesion molecule JAM-A has remarkable features: it can interact with itself if expressed on two opposing cell types. Furthermore, if JAM-A is shed by a cell, the soluble form of the JAM-A molecule can bind to cell-bound JAM-A, which in turn even enhances its binding capacity. What ensues is a vicious cycle of malignant plasma cells expressing and shedding JAM-A, increasing JAM-A expression on endothelial cells and stimulating blood vessel formation. In turn, increasing numbers of JAM-A-overexpressing endothelial cells can now better bind malignant plasma cells, which now find more interaction partners and by increasing the multiple myeloma niche space can produce more JAM-A. Consequently, using different experimental models we found that blocking the adhesion molecule JAM-A would inhibit blood vessel formation, reduce JAM-A interactions and impair multiple myeloma disease progression. These therapeutic effects of blocking JAM-A were observed in preclinical models not in patients and, therefore, must be interpreted with caution. Nevertheless, our new findings may point towards a potential Achilles’ heel of multiple myeloma that might be exploited therapeutically in the future.

This work was generally supported by the Bavarian Research Foundation within the research consortium FORTiTher and the German Research Council (DFG) consortium µbone.

Reference:

Solimando AG, Da Vià MC, Leone P, Borrelli P, Croci GA, Tabares P, Brandl A, Di Lernia G, Bianchi FP, Tafuri S, Steinbrunn T, Balduini A, Melaccio A, De Summa S, Argentiero A, Rauert-Wunderlich H, Frassanito MA, Ditonno P, Henke E, Klapper W, Ria R, Terragna C, Rasche L, Rosenwald A, Kortüm KM, Cavo M, Ribatti D, Racanelli V, Einsele H, Vacca A, Beilhack A. (2021). Halting the vicious cycle within the multiple myeloma ecosystem: blocking JAM-A on bone marrow endothelial cells restores the angiogenic homeostasis and suppresses tumor progression. Haematologica 106(7):1943-1956.