The Lipid Side of Bone Marrow Adipocytes: How Tumor Cells Adapt and Survive in Bone

Abstract

The combined in silico, pre-clinical, and clinical evidence shows that in adipocyte-rich tissues such as bone marrow, tumor cells rely on exogenous lipids for regulation of cellular energetics and adaptation to harsh metabolic conditions of the metastatic niche. Adipocyte-supplied lipids have a potential to alter the cell's metabolic decisions by regulating glycolysis and respiration, fatty acid oxidation, lipid desaturation, and PPAR signaling. The downstream effects of lipid signaling on mitochondrial homeostasis ultimately control life vs. death decisions, providing a mechanism for gaining survival advantage and reduced sensitivity to treatment. There is a need for future research directed towards identifying the key metabolic and signaling pathways that regulate tumor dependence on exogenous lipids and consequently drive the pro-survival behavior in the bone marrow niche.

Adipogenesis in Different Body Depots and Tumor Development

“…WAT adipocytes have fewer, elongated mitochondria selectively expressing proteins that support lipogenesis and degrade xenobiotics. Compared with WAT, BAT adipocytes possess larger mitochondria featured by a higher expression level of UCP1, fatty acid oxidation-related enzymes such as acetyl-CoA dehydrogenase and catabolic metabolism (Diedrich et al, 2018;Lee et al, 2019). The thermogenic capacity marker, UCP1, functions to uncouple the oxidative phosphorylation from ATP synthesis in the inner mitochondrial membrane and dissipate energy in the form of heat.…”

“…Beige adipocytes are also described as UCP1 + cells with a dense mitochondrial network and multilocular lipid droplets (Figure 1). In physiological conditions, beige adipocytes act as white adipocytes, while in response to environmental factors such as cold exposure, exercise, cancer cachexia (CC), and tissue injury, their BAT-like function is induced independently of UCP1 (Diedrich et al, 2018;Ikeda et al, 2018). In contrast, the whitening of mouse BAT adipocytes upon temperature change, leptin receptor deficiency, β-adrenergic signaling inhibition, or lipase deficiency leads to decreased mitochondrial content and increased mitophagy (the autophagic degradation of mitochondria) promoting WAT-like tissue formation (Altshuler-Keylin et al, 2016;Ikeda et al, 2018;Kotzbeck et al, 2018).…”

“…Moreover, metastatic tumor cells interact with medullar adipocytes forming a specific metastatic niche in BM (Morris and Edwards, 2016;Diedrich et al, 2018). BMAT increases during an early stage of murine myeloma, where marrow adipocytes localize along the tumor-bone interface at later stages of the disease.…”

“…As such, metastatic prostate tumor cell-derived IL-1β induced prostaglandin E2 expression and lipolysis in BM adipocytes, coinciding with the pro-survival pathway activation in tumor cells ( Herroon et al, 2019 ). Also, BMAT-induced reactive oxygen species (ROS) production and the heme oxygenase-1 overexpression resulted in the activation of survival molecules survivin (BIRC5) and Bcl-xl in metastatic prostate and breast tumor cells ( Diedrich et al, 2018 ; Herroon et al, 2018 ). A recent study interestingly suggests that marrow malignancy might affect the adipogenic commitment of resident mesenchymal progenitors, since AML-derived MSCs showed increased adipogenesis, supporting the survival of leukemia progenitor cells ( Azadniv et al, 2020 ).…”

Three‐dimensional intravital imaging in bone research

“…It should be noted that other cell types in bone also play a role in bone biology, such as neuron cells. More recently, adipocytes in the BM space have been demonstrated to exert impacts on osteogenesis , hematopoiesis and tumor survival . However, IVI has not been employed for investigation of fluorescence labeled neuron cells and adipocytes in bone.…”