Multiple Myeloma (MM) is a plasma cell malignancy in which monoclonal plasma cells accumulate in the bone marrow (BM). The interaction between the BM cells and MM is pivotal to the progression of MM and forms therefore an attractive target. The BM aids in the growth of these malignant cells by providing them with necessary growth factors & nutrients, creating an immune compromised environment and inducing drug resistance.
In this dissertation, we aimed to explore the role and function of exosomes in MM. We first demonstrated that exosomes are implicated in MM bone disease by inhibiting osteoblast differentiation and stimulating osteoclast function.
More importantly, we also showed an added effect in vivo of exosome inhibition to bortezomib on tumor load in the 5TGM1 mouse model.
Secondly, we performed a lipidomic analysis on peripheral plasma of MM patients. We found several differences in lipid composition between healthy and MM human plasma. This led to the discovery and evaluation of a new therapeutic target in MM, i.e. acid sphingomyelinase (ASM), which can be transported between cells by MM exosomes. The inhibition of this enzyme by amitriptyline led to an increased drug sensitivity to both melphalan and bortezomib.
This study further uncovers the role of exosomes secreted by MM cells in inducing osteolysis and drug resistance and confirms that these exosomes present an attractive target in the treatment of MM.
- Exosomal communication
- Multiple Myeoma
- melphalan, brotezomib