JAM-A as a prognostic and therapeutic target for multiple myeloma
An adhesion molecule on multiple myeloma cells correlates with patient outcome and proves as a promising new target for cancer therapy. Today, the respected journal Leukemia published our new study on JAM-A by lead authors Antonio Solimando and Andreas Brandl.
A perfect match of a physician scientist from Italy and a German researcher turned out as extremely fruitful. Dr. Antonio Solimando, scholar of the Aldo Moro’—Internal Medicine Residency Program from the University of Bari entered the residency program at the Department of Medicine II at Würzburg University. At that time, he also joined the Beilhack lab and teamed up with an experienced molecular immunologist in the group, Dr. Andreas Brandl. Both scientists set out to investigate how multiple myeloma, a cancer of bone marrow plasma cells, depends on cell interactions with the bone marrow microenvironment to progress and disseminate. Supported by a functional screening approach of scientific collaborators Prof. Franz Jakob and assistant professor Regina Ebert, both members of our DFG SkelMet research consortium, our interdisciplinary team stumbled upon a fascinating cell adhesion molecule, termed JAM-A (junctional adhesion molecule A). In healthy individuals, JAM-A has important functions in lymphocyte development. However, its aberrant expression has already been associated with various types of cancer.
Following a vigorous retrospective analysis in patients our new study uncovers that JAM-A correlates with the disease outcome in multiple myeloma patients: When multiple myeloma patients presented with high JAM-A expression levels (in serum and on cancer cells), their outcome was significantly worse when compared to patients with low JAM-A expression levels. Intrigued by these clear-cut findings Dr. Solimando and Dr. Brandl asked whether therapeutic interference with JAM-A would affect disease biology in vitro and in vivo. Indeed, inhibition of JAM-A on human multiple myeloma cells resulted in impaired myeloma cell migration, colony formation, chemotaxis, proliferation and viability. Furthermore, when both scientists treated multiple myeloma bearing mice with an anti-JAM-A monoclonal antibody they could impair tumor progression.
These results are intriguing as they pinpoint a potential Achilles heel of multiple myeloma. To date, this plasma cell malignancy is still considered as an incurable disease, partially because of rapidly arising cancer sub-clones .However, it appears that multiple myeloma’s initial progression highly depends on interactions with the bone marrow microenvironment. Now, by disrupting an important adhesion molecule such as JAM-A emerges as highly attractive to abrogate interactions between multiple myeloma cells and the cancer supporting bone marrow cancer niche environment. Clearly, these findings warrant further experiments to pursue therapeutic targeting of JAM-A, e.g. through the optimal combination with other therapeutic strategies to prevent MM progression, dissemination and drug resistance. Furthermore, this new collaborative study between Italian and German scientists suggests JAM-A as a biomarker for multiple myeloma patients, and soluble JAM-A as a serum-based marker for clinical stratification.
This study was generously supported by grants of the Deutsche Forschungsgemeinschaft (FOR-1586, CRU-216). Scientists from the University of Würzburg joined their research effort with researchers from the University of Bari, Italy.
Solimando AG*, Brandl A*, Mattenheimer K, Graf C, Ritz M, Ruckdeschel, Stühmer T, Mokhtari Z, Rudelius M, Dotterweich J, Bittrich M, Desanti V, Ebert R, Trerotoli P, Frassanito MA, Rosenwald A, Vacca A, Einsele H, Jakob F, Beilhack A. (2017). JAM-A as a prognostic factor and new therapeutic target in multiple myeloma. Leukemia (advance online publication 24 October 2017) doi: 10.1038/leu.2017.287
*These authors contributed equally to this work.