Tumor-associated macrophages (TAMs) influence lung tumor development by inducing immunosuppression. Transcriptome analysis of TAMs isolated from human lung tumor tissues revealed an up-regulation of the Wnt/beta-catenin pathway. These findings were reproduced in a newly developed in vitro "trained" TAM model. Pharmacological and macrophage-specific genetic ablation of beta-catenin reprogrammed M2-like TAMs to M1-like TAMs both in vitro and in various in vivo models, which was linked with the suppression of primary and metastatic lung tumor growth. An in-depth analysis of the underlying signaling events revealed that beta-catenin-mediated transcriptional activation of FOS-like antigen 2 (FOSL2) and repression of the AT-rich interaction domain 5A (ARID5A) drive gene regulatory switch from M1-like TAMs to M2-like TAMs. Moreover, we found that high expressions of beta-catenin and FOSL2 correlated with poor prognosis in patients with lung cancer. In conclusion, beta-catenin drives a transcriptional switch in the lung tumor microenvironment, thereby promoting tumor progression and metastasis.
- Sarode, P.
- Zheng, X.
- Giotopoulou, G. A.
- Weigert, A.
- Kuenne, C.
- Gunther, S.
- Friedrich, A.
- Gattenlohner, S.
- Stiewe, T.
- Brune, B.
- Grimminger, F.
- Stathopoulos, G. T.
- Pullamsetti, S. S.
- Seeger, W.
- Savai, R.
