Canonical and alternative functions of low-density lipoprotein in multiple myeloma - PROJECT SUMMARY Multiple myeloma (MM) remains an incurable malignancy in most patients, who will eventually relapse and become refractory to existing therapies. There is thus a critical need for therapeutic innovations that maintain remission and preserve patient quality of life. The tumor microenvironment (TME) of MM is within hypoxic bone marrow, which is intriguing because membrane biogenesis for proliferation is limited by available cholesterol. The synthesis of cholesterol is energy- and oxygen-intensive, and limited supply leads to resource competition between constantly dividing tumor and hematopoietic cells. This nutrient tug-of-war between tumor and nontumor cells in the MM-TME is evidenced by high rates of anemia and infection in MM patients. Separately, altered immune cell behavior results in immunosuppression, which is common in advanced and relapsing MM, and therapeutically underserved. Epidemiolocal studies indicate that low levels of plasma cholesterol are linked with MM progression, likely reflecting the high demand for sterols in the TME. All cells can rapidly increase cellular sterol levels and stimulate membrane biosynthesis through uptake of cholesterol-rich low-density lipoprotein (LDL). Most recently, it has been published that LDL also transport small RNAs that promote macrophage polarization by activating an endosomal sensor of RNA, toll-like receptor 8 (TLR8). Researchers demonstrated that pharmacologic antagonism of TLR8 shifted the immune landscape within atherosclerotic plaques and reduced disease burden in hyperlipidemic mice. Taken together, LDL is a nutrient-dense particle capable of supporting cell proliferation, and a source of extracellular sRNA capable of modulating immune cell function. The goal of this Stephen I. Katz Early-Stage Investigator Grant is to 1) determine whether LDL’s canonical functions in lipid transport directly enable MM growth, progression and therapeutic resistance, and 2) investigate whether LDL’s transport of small RNAs indirectly enables MM progression through activation of TLR8 in host leukocytes to create an immunosuppressive TME. In agreement with the funding mechanism, this proposal represents an ambitious new direction for our laboratory supported by rigorous work in the literature and an ensemble of experienced collaborators and clinicians that reflect the tremendous environment for translational MM research at our institution. We will harness this translational power by using innovative approaches to humanize lipoprotein metabolism in proven pre-clinical models of MM, and by combining state-of-the-art bioinformatic, imaging, and single-cell immune profiling approaches, to test the therapeutic synergy of safe, effective, and FDA-approved, LDL-lowering drugs with standard-of-care chemotherapy. Mice are used in this study because it is not possible to fully recapitulate the complex patho-physiological state of myeloma disease, which involves multiple cells, tissues and organs, using cultured cell models. The validity of mice as an animal model for studying the pathophysiology and treatment of myeloma disease has been supported by extensive literature showing that cellular and molecular features of myeloma disease in mice are similar to those in humans. Upon completion, this award will fill a critical gap in knowledge of how LDL contributes to a pro-malignant TME, and more specifically how lipoprotein disequilibrium contributes to immunosuppression in MM. We envision that these data will be leveraged to open many new research opportunities for diagnostic and therapeutic approaches for MM, and perhaps, other malignancies.
