Tumor-Associated Macrophages Serve as an Acetate Reservoir to Drive Hepatocellular Carcinoma Metastasis
SHEN Li, LU Ming*
Metabolic reprogramming is a cardinal driver of tumor progression and metastasis. Accumulation of acetyl-CoA has emerged as a pervasive metabolic hallmark of metastatic cancers. While many malignant cells avidly import acetate to sustain high acetyl-CoA pools, the cellular source of extracellular acetate remains enigmatic. Here, using orthotopic and cell-based HCC (hepatocellular carcinoma) models, the researchers demon- strate that TAMs (tumor-associated macrophages) are both necessary and sufficient to trigger acetate accumulation in malignant hepatocytes. Mechanistically, TAMs activate a lipid peroxidation-ALDH2 (aldehyde dehydrogenase 2) axis that converts lipid-derived aldehydes into acetate, which is subsequently released and is taken up by HCC cells. TAMs-derived acetate fuels acetyl-CoA synthesis, thereby enhancing H3ac (H3 acetylation) and potentiating EMT (epithelial-to-mesenchymal transition) and HCC cell motility in vitro. Genetic or pharmacologic blockade of ALDH2 or lipid peroxidation abrogates the pro-migratory activity of TAMs-secreted acetate. Moreover, TAMs- specific deletion of ALDH2 in an orthotopic mouse model markedly reduced lung metastasis of HCC. Finally, the researchers identify tumor cell-derived lactate as the initiating signal that elevates ROS (reactive oxygen species) levels in TAMs, thereby igniting the lipid peroxidation-ALDH2 pathway. These findings unveil a previously unrec- ognized “lactate-lipid peroxidation-acetate” metabolic circuitry between HCC cells and TAMs, establish TAMs as a critical acetate supplier within the tumor microenvironment, and nominate macrophage ALDH2 as a tractable thera- peutic target for preventing HCC metastasis.
CN
EN