Fat cells may help myeloma survive when glucose is scarce, study finds

When glucose is scarce, fat cells can produce beta-OHB, a molecule that helps myeloma cells survive metabolic stress, a new study found.

The study, “Adipocyte-derived β-hydroxybutyrate confers metabolic resilience in multiple myeloma,” was published in Nature Communications. The findings shed new light on the connection between myeloma and obesity, and point to this fat cell-myeloma pathway as a potential treatment target.

“Our study … reveals an adipocyte [fat cell]-myeloma metabolic crosstalk mediated by [beta]-OHB, uncovering a druggable pathway to overcome metabolic resilience in multiple myeloma,” the researchers wrote.

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Myeloma is a form of blood cancer in which plasma cells, a type of immune cell, grow out of control in the bone marrow. It’s been well-established that people with obesity are at higher risk of myeloma. However, the biological connection between myeloma and obesity is poorly understood.

Cancer cells require a lot of energy to fuel their growth. Many cancer cells rely heavily on glucose, a type of sugar, to support their growth and survival. Reducing glucose availability can place these cells under metabolic stress and limit tumor growth.

Working in mouse models, researchers in China used a compound to mimic glucose deprivation and create metabolic stress. This reduced myeloma tumor burden in mice fed a normal diet, but had a much weaker effect in mice with diet-induced obesity. The findings suggested that adipocytes, or fat cells, were helping myeloma cells withstand this metabolic stress.

In further experiments, the researchers found that glucose deprivation increased ketone production in adipocytes, including production of beta-OHB (beta-hydroxybutyrate). Beta-OHB then helped myeloma cells maintain the survival protein IRF4 and survive under glucose-deprived conditions.

Under glucose deprivation, a metabolic enzyme called AMPK becomes activated in myeloma cells. This enzyme sets off a chain of events that results in the breakdown of IRF4, a protein that promotes myeloma cell survival. Lower IRF4 levels make it harder for myeloma cells to survive this metabolic stress. But beta-OHB can counteract this process: myeloma cells use OXCT1 and NAT10 to stabilize IRF4, helping the cancer cells survive under glucose-deprived conditions.

“Metabolic stressors suppress myeloma by inducing IRF4 degradation, while concurrently stimulating adipocyte [production of beta-OHB], which counteracts this degradation to promote survival,” the researchers wrote.

Building on these findings, the researchers found that combining a drug that activates AMPK with drugs targeting OXCT1 or NAT10 led to synergistic antitumor activity in animal models. The researchers said the findings support further study of combining metabolic stress — through approaches such as glycolysis inhibition, intermittent fasting, or AMPK activation — with drugs that block OXCT1 or NAT10 as a potential treatment strategy for myeloma.