Exploring the abundance of lipid droplets and their potential as therapeutic targets in Multiple Myeloma (MM)
Aim
In this project, we will investigate the abundance of lipid droplets (LDs) in MM cell lines and primary cells by flow cytometry and confocal microscopy. Moreover, we will utilize different small-molecule inhibitors to target the lipid metabolism and evaluate the effects on cell viability and apoptosis. Our ultimate goal is to understand the role of the lipid metabolism in disease progression and to identify new therapeutic targets that would contribute to the management of MM.
Background
Multiple Myeloma (MM) is a heterogeneous hematological malignancy characterized by the aberrant proliferation of plasma cells within the bone marrow and the accumulation of monoclonal (M-spike) protein in the blood and serum. It is the second most common hematological malignancy with 660 new myeloma cases diagnosed each year in Sweden. Despite the introduction of novel therapies such as immunomodulating agents, proteasome inhibitors, corticosteroids and alkylators, MM still remains largely incurable. Hence, there is an urgent need to unravel the molecular mechanisms that drive heterogeneous treatment response and resistance in MM patients.
Metabolic reprogramming is considered as one of the major cancer hallmarks highlighting the crucial role of lipid metabolism in cancer cell survival and proliferation. Lipids are stored in lipid droplets (LDs) which are cytoplasmic organelles produced at the endoplasmic reticulum (ER) and ranging from 0.4 to 100 μm. Recently, it was shown that cancer cells exhibit an increased number of lipid droplets to cope with the high proliferation rate and energy needs. Such an increase in the LD content could be mediated by either the activation of endogenous synthesis or the uptake of exogenous lipids. Since the lipid metabolism plays a key role in cancer growth and survival, it could serve as an interesting therapeutic target. In MM, the abundance and the role of LDs in malignant plasma cells have not been investigated yet.
Project plan
Our initial investigation will focus on exploring the abundance of lipid droplets in MM cells. By using the LD-specific fluorophore LD-BTD1, we will investigate whether myeloma cells have an increased number of lipid droplets compared to non-malignant cells. To validate our findings, we will perform the LD staining in primary plasma cells isolated from the bone marrow of healthy donors and myeloma patients. Moreover, we will investigate the effects of lipid metabolism inhibition on cell viability and apoptosis of MM cells by blocking either the exogenous uptake of lipids or de novo lipogenesis. The ultimate goal will be to combine these inhibitors with one of the chemotherapies used in the clinic to achieve an additive and potentially synergistic effect that could benefit myeloma patients. In vivo experiments will also be performed in the 5T33U murine myeloma model or in a cell line-derived xenograft (CDX) model to reinforce the clinical benefits of this combinatorial strategy.
If you are a driven and highly motivated student with an interest in lipid metabolism and cancer biology, please don’t hesitate to contact us.
Contact details:
Patrick Nylund, PhD: patrick.nylund@igp.uu.se
Stefania Iliana Tziola, PhD student: stefania.tziola@igp.uu.se