Adipocytes and metabolism: Contributions to multiple myeloma

• Published in: Journal of bone oncology 2024-06, Vol.46, p.100609, Article 100609
• Main Authors: Fairfield, Heather, Karam, Michelle, Schimelman, Allyson, Qiang, Ya-Wei, Reagan, Michaela R.
• Format: Article
• Language: English
• Subjects: Adipocytes; Drug resistance; Fatty acids; Metabolism; Multiple myeloma; Research Paper
• ISSN: 2212-1374; 2212-1366; 2212-1374
• DOI: 10.1016/j.jbo.2024.100609

•How can bone marrow adipocytes be modulated to affect cancer cell growth or drug resistance?•What roles do adipocyte-derived fatty acids play in cancer within the bone marrow?•Will targeting cell-intrinsic or microenvironment-derived fatty acid binding proteins (FABPs), ACSLs (acyl-CoA synthetase long chain family members), lactate metabolism, or other metabolic pathways lead to novel cancer therapies?•Can we target tumor cell metabolism specifically, while sparing healthy cells? Obesity contributes to many cancers, including breast cancer and multiple myeloma, two cancers that often colonize the bone marrow (BM). Obesity often causes metabolic disease, but at the cellular level, there is uncertainty regarding how these shifts affect cellular phenotypes. Evidence is building that different types of fuel affect tumor cell metabolism, mitochondrial function, and signaling pathways differently, but tumor cells are also flexible and adapt to less-than ideal metabolic conditions, suggesting that single-pronged attacks on tumor metabolism may not be efficacious enough to be effective clinically. In this review, we describe the newest research at the pre-clinical level on how tumor metabolic pathways and energy sources affect cancer cells, with a special focus on multiple myeloma (MM). We also describe the known forward-feedback loops between bone marrow adipocytes (BMAds) and local tumor cells that support tumor growth. We describe how metabolic targets and transcription factors related to fatty acid (FA) oxidation, FA biosynthesis, glycolysis, oxidative phosphorylation (OXPHOS), and other pathways hold great promise as new vulnerabilities in myeloma cells. Specifically, we describe the importance of the acetyl-CoA synthetase (ACSS) and the acyl-CoA synthetase long chain (ACSL) families, which are both involved in FA metabolism. We also describe new data on the importance of lactate metabolism and lactate transporters in supporting the growth of tumor cells in a hypoxic BM microenvironment. We highlight new data showing the dependency of myeloma cells on the mitochondrial pyruvate carrier (MPC), which transports pyruvate to the mitochondria to fuel the tricarboxylic acid (TCA) cycle and electron transport chain (ETC), boosting OXPHOS. Inhibiting the MPC affects myeloma cell mitochondrial metabolism and growth, and synergizes with proteosome inhibitors in killing myeloma cells. We also describe how metabolic signaling pathways intersect established survival and