Bone marrow adipocytes in cancer: Mechanisms, models, and therapeutic implications

Adipose tissue is the primary site of energy storage in the body and a key regulator of metabolism. However, different adipose depots exhibit distinct molecular and phenotypic characteristics that have yet to be fully unraveled. While initially considered inert, bone marrow adipocytes (BMAs) have been recognized as key regulators of bone homeostasis, and more recently bone pathologies, although many unknowns remain. In this review, we summarize the current knowledge on BMAs, focusing on their distinct characteristics, functional significance in bone physiology and metabolism, as well as their emerging role in cancer pathogenesis. We present and discuss the current methodologies for investigating BMA-cancer interactions, encompassing both in vitro 3D culture systems and in vivo models, and their limitations in accurately replicating the phenotypes and biological processes of the human species. We highlight the imperative for advancing towards humanized models to better mimic the complexities of human physiology and disease progression. Finally, therapeutic strategies targeting metabolism or BMA-secreted factors, such as anti-cholesterol drugs, hold considerable promise in cancer treatment. We present the synergistic avenue of combining conventional cancer therapies with agents targeting adipocyte signaling to amplify treatment efficacy. Developing preclinical models that more faithfully replicate human pathological and physiological processes will lead to more accurate mechanistic understanding of the role of BMAs in bone metastasis and lead to more relevant preclinical drug screening.