Multiple Myeloma Support from the Microenvironment: Bone Marrow Adipocytes and the Fatty Acid Binding Proteins
Michaela Reagan
PhDMaine Medical Center
Project Term: July 1, 2024 - June 30, 2029
Our project’s goal is to change how multiple myeloma is understood and treated by interrogating a novel part of the cellular “soil” (the bone marrow adipocyte), in which myeloma cells, or “seeds”, land and grow. We will discover new forms of cancer drug resistance that are driven by adipocyte-derived factors and the fatty acid binding proteins. This work will expose new ways to overcome drug resistance to improve survival and quality of life for myeloma and other hematological cancer patients.
The Reagan lab specializes in the study of an incurable plasma cell malignancy: multiple myeloma (MM). Myeloma cells grow in the rich soil of the bone marrow (BM), first very slowly, causing no damage or symptoms, and then more quickly and aggressively, causing degradation of the bone, clonal evolution and adaptation, and the appearance of drug resistant clones. Our lab collaborates with researchers in the cancer, bone, and bone marrow adiposity fields to better understand the biology of the cancer BM microenvironment, to develop new knowledge about how myeloma cells home to the bone, proliferate, remain dormant, become drug resistant, and spread to other locations. The risk of developing myeloma is greater in older individuals and obese or overweight people. These patients also typically have more bone marrow adipose (fat) tissue, than younger or leaner individuals. However, the ways in which bone marrow adipocytes (BMAds), which are often physically neighboring myeloma cells, modulate MM progression are poorly understood. The Reagan lab has been dedicated to understanding MM with a specific focus on how obesity and BMAds contribute to the development and progression of MM. Through this work, we discovered that the FABPs (fatty acid binding proteins) are a new therapeutic target in MM. We found many ways in which BMAds support and induce drug resistance in myeloma cells and observed that myeloma cells hijack and induce senescence in BMAds, creating a feedback loop to further support the tumor. We have also developed novel, three-dimensional (3D), tissue engineered, silk scaffold-based cancer models that allow us to study BMAd and myeloma cell interactions. Moreover, we have all of the current gold-standard myeloma models and we increase our cell line and myeloma primary patient sample inventories yearly. A future project in our lab is understanding how diet-induced obesity contributes to MM survival though immune system modulation and tumor cell metabolic changes using single cell RNA-sequencing and flow cytometric BM analysis. Since immunotherapies have demonstrated great promise for MM in recent years, this work may support development of new immunotherapies or improved combinations of current immunotherapies. Overall, we aim to identify molecules and mechanisms driving myeloma growth and drug resistance, identify feedback loops between host and cancer cells, and propose paradigm-shifting concepts to guide the development of new anti-MM therapeutics.