Reprogramming of tumor-associated macrophages by targeting β-catenin/FOSL2/ARID5A signaling: A potential treatment of lung cancer

Abstract

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/β-catenin pathway. These findings were reproduced in a newly developed in vitro “trained” TAM model. Pharmacological and macrophage-specific genetic ablation of β-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 β-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 β-catenin and FOSL2 correlated with poor prognosis in patients with lung cancer. In conclusion, β-catenin drives a transcriptional switch in the lung tumor microenvironment, thereby promoting tumor progression and metastasis.

Tumor‑associated macrophages in lung cancer: Friendly or evil? (Review)

“…Accumulating evidence has suggested that TAMs originate from blood monocytes, and are recruited at tumor sites by tumor-derived chemotactic signals, including monocyte chemo-attractant protein-1 (MCP-1), which is also known as CCL2 ( 11 – 13 ). Furthermore, a small wave develops from in situ monocyte-macrophage proliferation and splenic monocytes.…”

“…Clinical studies have suggested that increased TAM density correlates with a poor prognosis in solid tumors ( 5 , 7 , 8 ) Several animal model experiments have validated this observation by demonstrating that increased TAM density is associated with tumor progression and metastasis, and overexpression of macrophage growth factors or chemokines ( 9 , 10 ). The deletion or re-differentiation of TAMs enhances immune cell-mediated anti-tumor responses and benefits from chemotherapy ( 11 – 13 ). Therefore, targeting TAMs may be at the forefront of lung cancer research and a novel strategy for lung cancer therapy.…”

Immune Modulation in Lung Cancer: Current Concepts and Future Strategies

“…Under the influence of tumor-derived type-2 cytokines, colony-stimulating factor 1 (CSF-1 or M-CSF), CCL2, and CCL4, adjacent lymphocytes become Th2-shifted, while tissue-resident macrophages and blood monocytes are attracted and converted to the M2 phenotype [40-44], as demonstrated by analysis of human lung cancer specimens and in vitro studies. The phenotypic switch of macrophages appears to rely on epigenetic changes [45] and Wnt signaling [46] and is of key importance, because tumor-associated M2 macrophages (TAMs) orchestrate several vicious cycles in the TME [47, 48] to promote: (i) tumor-cell growth by secretion of epidermal growth factor (EGF), matrix metallopeptidases, Wnt family member (WNT) 5A, cathepsin B, semaphorin 4D, and IL-1β [49]; (ii) DNA damage by suppressing p53 through macrophage migration inhibitory factor [50]; (iii) angiogenesis, tumor-endothelial cell dysfunction, and lymphangiogenesis by secretion of VEGF, IL-8, and matrix metallopeptidase-9 [51-53]; (iv) invasion, epithelial-to-mesenchymal transition, and metastasis [54-57]. Besides, TAM-derived TGFβ and chemokines synergize with contact signals from tumor cells to convert tissue-resident fibroblasts, mast cells, and blood-derived neutrophils to smooth-muscle actin-α-expressing cancer-associated fibroblasts (CAFs), tumor-associated mast cells (TAMCs), and tumor-associated neutrophils (TANs), respectively, whose secretome amplifies all tumorigenic effects [58-60].…”

Fibroblast Growth Factor—14 Acts as Tumor Suppressor in Lung Adenocarcinomas

“…For RNA-seq, as previously described [28], we isolated RNA from A549-FGF14 overexpressing cells and empty vector control cells. The statistical significance of differentially expressed genes (DEGs) were analyzed based on a combination of absolute expression (basemean), divergence (log2 fold change, log2fc), and significance (adjusted p-value, padj).…”