Project Details
Projekt
Deciphering pathogenesis, treatment and reversibility of myeloma bone disease at a single cell resolution
Applicants
Dr. Maximilian Merz; Dr. Heike Weidner
Subject Area
Hematology, Oncology
Term
since 2022
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 491584344
Multiple myeloma is a monoclonal plasma cell disease of the bone marrow in which up to 80% of newly diagnosed patients have osteolytic lesions. In the last years, treatment options for patients with multiple myeloma have improved by providing anti-resorptive treatment in addition to conventional therapy to reduce the activity of bone-resorbing osteoclasts. However, subsequent improvement in bone phenotype rarely occurs despite achieving deep remission and the patients suffer from an impaired quality of life. Why multiple myeloma bone lesions do not often show recalcification has not been sufficiently studied. Therefore, the proposed project will investigate the pathomechanism of bone destruction before and after therapy using longitudinal samples. We postulate that the failure to calcify is due to impaired bone formation. Fibroblast growth factor-23 (FGF-23) may play an important role, as plasma levels of FGF-23 are increased in multiple myeloma. To test our hypothesis, bone marrow aspirates, bone biopsies, and plasma samples will be collected at primary diagnosis as well as before and after autologous stem cell transplantation. Longitudinal changes in the malignant plasma cell compartment and surrounding bone marrow microenvironment from patients with multiple myeloma will be studied by single cell RNA and surface proteome sequencing. To identify crucial factors that are responsible for the lack of bone healing, we will compare patients with and without recalcification of osteolytic lesions after therapy. The extent of bone disease will be assessed using bone mineral density measurements and computed tomography. Bone morphology will be characterized further with histology, analyzing not only osteoclasts and osteoblasts but also bone mineralization, which has an influence on bone formation. The obtained data will be correlated with blood parameters (hemoglobin, red blood cells) and bone-specific plasma parameters (e.g. FGF-23, OCN, CTX), again longitudinal changes in patients with multiple myeloma are important. In order to investigate the influence of autocrine/paracrine factors and therapy on osteoblast function as well as the potential for recalcification, we will develop an in vitro triple co-culture of osteoblasts, osteoclasts and plasma cells. Furthermore, the model will be used to validate findings from single cell experiments and to study the differentiation potential of patient-derived mesenchymal stem cells before and after therapy as well as the influence of induction therapy on healthy cells. Besides myeloma-specific therapeutic interventions, we will evaluate the blockage of FGF23. If single cell sequencing identifies candidates associated with impaired osteoblast function, their expression will be regulated in triple co-culture. Within the current study, factors responsible for the failure of bone regeneration after successful therapy of newly diagnosed multiple myeloma will be identified.
DFG Programme
Priority Programmes
