Involvement of ACACA (acetyl-CoA carboxylase α) in the lung pre-metastatic niche formation in breast cancer by senescence phenotypic conversion in fibroblasts

Abstract

BackgroundImpairment of metabolism is strongly associated with the development of cancer. However, the role of metabolic reprogramming in the remodeling of pre-metastatic niche (PMN), a key step in metastasis, is still unknown. We aimed to investigate the metabolic alternation during lung PMN formation.MethodsWe assessed the transcriptomes and lipidomics of lung of MMTV-PyVT mice by microarray and liquid chromatography-tandem mass spectrometry before lung metastasis. The validation of gene or protein expressions was performed by real-time quantitative polymerase chain reaction, immunoblot and immunohistochemistry. The lung fibroblasts were isolated from mice and then co-cultured with breast cancer to identify the influence of cancer on the change of lung fibroblasts in PMN.ResultsWe demonstrated changes in the lipid profile and several lipid metabolism genes in the lungs of breast cancer-bearing MMTV-PyVT mice before cancer spread. The expression of ACACA (acetyl-CoA carboxylase α) was downregulated in the lung fibroblasts, which contributed to changes in acetylation of protein’s lysine residues and the synthesis of fatty acid. The downregulation of ACACA in lung fibroblasts triggered a senescent and inflammatory phenotypic shift of lung fibroblasts in both in vivo and in vitro models. The senescence-associated secretory phenotype of lung fibroblasts enabled the recruitment of immunosuppressive granulocytic myeloid-derived suppressor cells into the lungs through the production of CXCL1 in the lungs. Knock-in of ACACA prevented lung metastasis in the MMTV-PyVT mouse model, further supporting that ACACA was involved in the remodeling of the lung PMN.ConclusionsTaken together, these data revealed a mechanism by which ACACA downregulation directs the formation of an immunosuppressive lung PMN in breast cancer.