Gericht op syntenin-syndecaan (CD138) exosome omzet voor multiple myeloma therapie

Multiple myeloma is a hematological cancer characterized by the accumulation of malignant plasma cells in the bone marrow (BM) microenvironment. Despite significant advancements in the treatment of MM with drugs like the proteasome inhibitor bortezomib, the disease remains incurable and ultimately develops resistance. The development of bortezomib resistance involves multiple mechanisms and is driven by various factors. Unfortunately, effective strategies to overcome this resistance are still lacking. Emerging evidence has shown that stroma-MM mediated communication by sEVs and cytokines within the BM microenvironment play critical roles in this process. Syntenin, as a scaffold protein, is not only highly expressed in various cancers but also plays an important role in regulating the secretion of small extracellular vesicles. Thus, targeting syntenin represents a promising therapeutic strategy for overcoming extrinsic bortezomib resistance in MM. On the other hand, metabolic plasticity enables MM cells to adapt to therapeutic stress and contributes significantly to bortezomib resistance. In this sense, pyruvate is an interesting metabolite, sitting at the crossroads between mitochondrial energy production and mitochondrial stress. Therefore, pyruvate could play a role in metabolic bortezomib resistance and could therefore serve as a novel orally available therapeutic. In this study, we first focused on disrupting BMSC-MM communication within the bone marrow microenvironment. We demonstrated that genetic and pharmacological inhibition of syntenin in BMSCs altered their secretion of sEVs and IL-6, thereby reducing BMSC-induced bortezomib resistance in MM cells via modulation of the STAT3, MAPK, and AKT-mTOR signaling pathways. Moreover, the syntenin-PDZ2 inhibitor SyntOFF, in combination with bortezomib, significantly suppressed MM progression in the 5TGM1 murine model. Next, we investigated tumor-intrinsic drug resistance by examining the role of pyruvate. We observed that pyruvate was taken up by MM cells in a time-dependent manner and enhanced OXPHOS. When combined with bortezomib, pyruvate increased ROS and activated the ATF4-CHOP stress pathway, promoting MM cell apoptosis. In contrast, treatment with the OXPHOS inhibitor metformin also activated the integrated stress response but reduced mitochondrial ROS levels, ultimately diminishing the therapeutic efficacy of bortezomib. Collectively, these findings demonstrate how both tumor metabolic plasticity and stress response pathways influence MM sensitivity to bortezomib. In conclusion, this dissertation underscores on the one hand the critical role of the syntenin-regulated secretome in the progression of MM, offering valuable insights into targeting syntenin as a strategy to overcome bortezomib resistance. On the other hand, it highlights that metabolic plasticity not only confers a survival advantage to MM cells but also represents a promising therapeutic target for MM treatment.