Adhesion molecule interactions at the multiple myeloma interface

• Applicant: Dr. Andreas Brandl
• Subject Area: Hematology, Oncology
• Term: since 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 401253051

Multiple myeloma (MM) is a B-cell malignancy of clonally expanding antibody-producing plasma cells in the bone marrow with a significant impact on morbidity and mortality. Its incidence has steadily increased in the past decades. Though there have been therapeutic advances and major improvements in transplant techniques and new targeted therapies including novel agents (e.g. CAR-T cells, BiTEs, monoclonal antibodies, checkpoint inhibitors etc.) MM remains incurable and has the lowest 5-year survival rate (around 40%) among the three most occurring blood cancers (i.e., lymphoma, leukemia, and myeloma). MM is characterized by dissemination of multiple tumor cells throughout the bone marrow (BM). Disseminating malignant cells will need to migrate through connective tissue and enter the blood circulation using adhesion molecules such as integrins and Ig-like proteins, e.g. members of the Junctional Adhesion Molecule (JAM) family as described for common leukocytes. In recent years it became evident that signaling through adhesion molecules, including the Junctional Adhesion Molecule (JAM)-family members, regulates MM-BM-microenvironment interactions and that their overexpression/dysregulation is implicated in cancer pathogenesis. As the cell adhesion/migration system in the MM microenvironment has been recognized in supporting MM cell survival, progression, and development of drug resistance it became a key target in MM treatment. We postulate that family members of the junctional adhesion molecules (JAMs) play a pivotal role for MM survival, progression, and dissemination by facilitating the crosstalk with cells constituting the BM niche and will address the following specific aims: (I) 3D-remodeling of BM niche for visualization and manipulation of JAMs and additional molecule interactions under conditions which are close to the physiological disease status. (II) Targeting interacting molecules on the surrounding niche compartments (stroma/endothelium) and analyse the effects on survival and dissemination of MM. (III) Decipher the influence of adhesion molecules on disease outcome in combinatorial therapy. To achieve these aims we have established models of orthotopic syngeneic and humanized MM, non-invasive bioluminescence imaging and advanced microscopy techniques (e.g. high-resolution 3D light-sheet fluorescence microscopy). Imaging and microscopy will direct further cellular (e.g. multi-parameter flow cytometry, functional in vitro assays) and molecular in vitro analyses employing sophisticated 3D-co-culture setups based on multicellular micro-tissues. Our studies will help to refine therapeutic interventions, in particularly immunotherapy of MM bone disease. Ultimately, we envision that a better understanding of the pathophysiology of JAMs in MM will result in optimal combinatorial treatment strategies to overcome drug resistance in patients suffering from MM and help to establish semi-personalized anti-MM strategies.

• DFG Programme: Priority Programmes
• Subproject of: SPP 2084: µBONE: Colonization and interaction of tumor cells within the bone microenvironment
• Co-Investigator: Professor Dr. Andreas Beilhack