ADPGK-AS1 long noncoding RNA switches macrophage metabolic and phenotypic state to promote lung cancer growth.
Annika KargerSiavash MansouriMatthias S LeisegangAndreas WeigertStefan GüntherCarsten KuenneIlka WittigSven ZukunftStephan KlattBlerina AlirajLaura V KlotzHauke WinterPoornima MahavadiIngrid FlemingClemens RuppertBiruta WitteIbrahim AlkoudmaniStefan GattenlöhnerFriedrich GrimmingerHorst-Walter BirkSoni Savai PullamsettiSoni Savai PullamsettiPublished in: The EMBO journal (2023)
Long noncoding RNAs (lncRNAs) influence the transcription of gene networks in many cell types, but their role in tumor-associated macrophages (TAMs) is still largely unknown. We found that the lncRNA ADPGK-AS1 was substantially upregulated in artificially induced M2-like human macrophages, macrophages exposed to lung cancer cells in vitro, and TAMs from human lung cancer tissue. ADPGK-AS1 is partly located within mitochondria and binds to the mitochondrial ribosomal protein MRPL35. Overexpression of ADPGK-AS1 in macrophages upregulates the tricarboxylic acid cycle and promotes mitochondrial fission, suggesting a phenotypic switch toward an M2-like, tumor-promoting cytokine release profile. Macrophage-specific knockdown of ADPGK-AS1 induces a metabolic and phenotypic switch (as judged by cytokine profile and production of reactive oxygen species) to a pro-inflammatory tumor-suppressive M1-like state, inhibiting lung tumor growth in vitro in tumor cell-macrophage cocultures, ex vivo in human tumor precision-cut lung slices, and in vivo in mice. Silencing ADPGK-AS1 in TAMs may thus offer a novel therapeutic strategy for lung cancer.
Keyphrases
- endothelial cells
- long noncoding rna
- reactive oxygen species
- adipose tissue
- induced pluripotent stem cells
- single cell
- pluripotent stem cells
- oxidative stress
- signaling pathway
- gene expression
- stem cells
- cell therapy
- type diabetes
- cell proliferation
- skeletal muscle
- cell death
- mesenchymal stem cells
- copy number
- bone marrow
- dna methylation
- binding protein
- protein protein
- genome wide identification
- network analysis