Chinese researchers have revealed a mechanism that triggers metastasis of hepatocellular carcinoma (HCC)—the most common type of primary liver cancer—through the production of acetate by tumor-associated macrophages.
Acetate is important to cancer metastasis because it promotes the synthesis of acetyl-coenzyme A (acetyl-CoA), which is a pivotal metabolic intermediate in the catabolism of glucose, lipids, and amino acids, as well as the biosynthesis of lipids and the TCA cycle. Acetyl-CoA also functions as a signaling molecule due to its role in lysine acetylation. Increased acetyl-CoA production is characteristic of metastatic cancers.
Researchers have known that acetate levels in the blood are significantly lower than in cancer tissues, suggesting the presence of acetate-producing cells within the cancer microenvironment. However, the exact source of acetate in the cancer microenvironment was previously unclear.
Dr. LU Ming's group from the Shanghai Institute of Nutrition and Health of the Chinese Academy of Sciences, in collaboration with researchers from Huashan Hospital of Fudan University, has now identified a key acetate source by revealing how HCC cells trigger acetate secretion by tumor-associated macrophages (TAMs) through a metabolic interaction involving lactate and the lipid peroxidation–aldehyde dehydrogenase 2 (ALDH2) pathway.
The study was published in Nature Metabolism on Oct. 20.
Using primary TAMs and TAMs derived from cell lines, the researchers demonstrated that TAMs specifically promoted acetate accumulation in HCC cells. In an orthotopic HCC mouse model, depleting TAMs markedly decreased the intracellular acetate levels in HCC cells, highlighting TAMs as a key source of acetate in the cancer microenvironment.
Through metabolomic analysis and isotope tracing, the researchers revealed that TAMs generated and secreted acetate through the lipid peroxidation–ALDH2 pathway, and HCC cells subsequently took up acetate to synthesize acetyl-CoA, which in turn promoted histone H3 acetylation and epithelial-mesenchymal transition, thereby enhancing metastasis.
In vitro studies revealed that inhibiting ALDH2 or lipid peroxidation in TAMs effectively suppressed acetate-induced migration of HCC cells. Similarly, genetic ablation of Aldh2 in TAMs significantly reduced acetate levels in HCC cells and diminished lung metastases of HCC.
The researchers further showed that lactate secreted by HCC cells acted as an upstream signal that activated the lipid peroxidation–ALDH2 pathway in TAMs by elevating reactive oxygen species (ROS) levels.
This study reveals a novel metabolic interaction between HCC cells and TAMs, offering new mechanistic insights into how the local metabolic microenvironment influences the phenotypic plasticity of cancer cells. By identifying the lipid peroxidation–ALDH2 pathway as a key source of acetate in TAMs, this research highlights a potential therapeutic target for inhibiting liver cancer metastasis.
This work was supported by the National Key R&D Program of China and the National Natural Science Foundation of China.
