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Sarode, Poonam; Zheng, Xiang; Giotopoulou, Georgia A.; Weigert, Andreas; Kuenne, Carste; Guenther, Stefan; Friedrich, Aleksandra; Gattenloehner, Stefan; Stiewe, Thorsten; Bruene, Bernhard; Grimminger, Friedrich; Stathopoulos, Georgios T.; Pullamsetti, Soni Savai; Seeger, Werner; Savai, Rajkumar (2020): Reprogramming of tumor-associated macrophages by targeting beta-catenin/FOSL2/ARID5A signaling: A potential treatment of lung cancer. In: Science Advances, Vol. 6, No. 23, eaaz6105
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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.