Sarode, P.P.SarodeZheng, X.X.ZhengGiotopoulou, G.A.G.A.GiotopoulouWeigert, A.A.WeigertKuenne, C.C.KuenneGünther, S.S.GüntherFriedrich, A.A.FriedrichGattenlöhner, S.S.GattenlöhnerStiewe, T.T.StieweBrüne, B.B.BrüneGrimminger, F.F.GrimmingerStathopoulos, G.T.G.T.StathopoulosPullamsetti, S.S.S.S.PullamsettiSeeger, W.W.SeegerSavai, R.R.Savai2022-03-062022-03-062020https://publica.fraunhofer.de/handle/publica/26702810.1126/sciadv.aaz6105Tumor-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/v-catenin pathway. These findings were reproduced in a newly developed in vitro ""trained"" TAM model. Pharmacological and macrophage-specific genetic ablation of v-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 v-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 v-catenin and FOSL2 correlated with poor prognosis in patients with lung cancer. In conclusion, v-catenin drives a transcriptional switch in the lung tumor microenvironment, thereby promoting tumor progression and metastasis.en540571572journal article