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A5938 - Reprogramming of Tumor Associated Macrophages by Modulating Wnt β-Catenin Signalling in Lung Cancer
Author Block: P. Sarode1, X. Zheng1, A. Weigert2, A. Tretyn1, S. Guenther1, S. S. Pullamsetti1, F. Grimminger3, W. Seeger3, R. Savai1; 1Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany, 2Goethe-University Frankfurt, Institute of Biochemistry I, Frankfurt, Germany, 3Justus-Liebig-Univ Giessen, Giessen, Germany.
Data from clinical and experimental studies suggest that Tumor Associated Macrophages (TAMs) contribute to cancer progression and metastasis. We aim to identify and manipulate TAMs specific signalling pathways, which are responsible for shift of macrophage from pro-tumorigenic (M2 like-TAMs) to anti-tumorigenic (M1 like-TAMs). We established and characterized a novel in vitro model, training macrophages with tumor cell for 3 days (M1 like-TAMs) and 5 days (M2 like-TAMs). These M2 like TAMs showed reduced apoptosis in tumor cells, increased tumor cell migration and proliferation compared to M1 like-TAMs. RNA sequencing of M1 and M2 like-TAMs revealed differential activation of Wnt/β-catenin signalling. M2 like-TAMs showed significant upregulation in Wnt/β-catenin signalling. Immunostaining of β-catenin in TAMs of 70 human lung cancer sections revealed that β-catenin is activated in TAMs. Notably, interfering Wnt/β-catenin signalling in M2 like-TAMs by shRNAs of β-catenin, TNKS12 and β-catenin inhibitor resulted in cancer regression by phenotypic and functional switch of M2 like-TAMs to M1 like-TAMs. Interestingly, bone marrow derived macrophages of β-catenin knockout mice exhibit M1 like-TAMs phenotype. Therefore, to study the role of Wnt/β-catenin signalling in cancer cells/TAMs interplay in vivo, we treated adenocarcinoma xenograft model and metastasis lung tumor model with β-catenin inhibitor. Upon treatment, we observed significant reduction in tumor size and increased accumulation of M1 like-TAMs in tumor microenvironment. Interestingly, inhibition of Wnt/β-catenin signalling in TAMs from ex vivo isolated human and mouse lung tumors showed functional switch of M2 like-TAMs to M1 like-TAMs. Thus, intervention of Wnt/β-catenin signalling in TAMs will permit the development of new cancer therapeutics.