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.
- Karger, A.
- Mansouri, S.
- Leisegang, M. S.
- Weigert, A.
- Günther, S.
- Kuenne, C.
- Wittig, I.
- Zukunft, S.
- Klatt, S.
- Aliraj, B.
- Klotz, L. V.
- Winter, H.
- Mahavadi, P.
- Fleming, I.
- Ruppert, C.
- Witte, B.
- Alkoudmani, I.
- Gattenlöhner, S.
- Grimminger, F.
- Seeger, W.
- Pullamsetti, S. S.
- Savai, R.
Keywords
- Long noncoding RNAs
- Lung cancer
- Metabolic remodeling
- Tumor microenvironment
- Tumor-associated macrophages