β-Catenin signaling in alveolar macrophages enhances lung metastasis through a TNF-dependent mechanism

Abstract

The main cause of malignancy-related mortality is metastasis. Although metastatic progression is driven by diverse tumor-intrinsic mechanisms, there is a growing appreciation for the contribution of tumor-extrinsic elements of the tumor microenvironment, especially macrophages, which correlate with poor clinical outcomes. Macrophages consist of bone marrow–derived and tissue-resident populations. In contrast to bone marrow–derived macrophages, the transcriptional pathways that govern the pro-metastatic activities of tissue-resident macrophages (TRMs) remain less clear. Alveolar macrophages (AMs) are a TRM population with critical roles in tissue homeostasis and metastasis. Wnt/β-catenin signaling is a hallmark of cancer and has been identified as a pathologic regulator of AMs in infection. We tested the hypothesis that β-catenin expression in AMs enhances metastasis in solid tumor models. Using a genetic β-catenin gain-of-function approach, we demonstrated that (a) enhanced β-catenin in AMs heightened lung metastasis; (b) β-catenin activity in AMs drove a dysregulated inflammatory program strongly associated with Tnf expression; and (c) localized TNF-α blockade abrogated this metastatic outcome. Last, β-catenin gene CTNNB1 and TNF expression levels were positively correlated in AMs of patients with lung cancer. Overall, our findings revealed a Wnt/β-catenin/TNF-α pro-metastatic axis in AMs with potential therapeutic implications against tumors refractory to the antineoplastic actions of TNF-α.

Downregulation of IRF8 in alveolar macrophages by G-CSF promotes metastatic tumor progression

“…Myeloid IRF8 downregulation thus also precedes micro-metastasis in the autochthonous MTAG model. In contrast, in female WT mice bearing syngeneic implantable EMT6 (BALB/c) 50 or E0771.ML-1 (C57BL/6) 51 orthotopic tumors (average < 150 mm 3 ), lung micro-metastasis occurred while IRF8 expression remained intact in macrophages or monocytes of lung tissue and blood ( Figure S3 ). Our results indicate that IRF8 downregulation in macrophages and monocytes occurs in some, but not all preclinical mammary tumor models.…”

“…25 μM primer pairs ( Table S4 ) were used and assessed for a single melting curve per sample. Primer sequences were obtained from OriGene Technologies or published reports 44 , 51 , 87 , 91 , 93 , 94 and validated by NCBI primer BLAST. Relative expression was normalized to Ppia expression and calculated using the equation POWER(2, Ppia mean – experimental value).…”

Macrophage heterogeneity and its interactions with stromal cells in tumour microenvironment

“…What about TRM? Some research has proved TRMs also involved in tumor progression, especially in lung pre-metastasis niche [ 183 , 184 ], but few studies concentrated on their interactions with stromal cells. Exploring TRMs and their cellular communications in TME may contribute to understanding macrophage heterogeneity and cell crosstalk.…”

The roles of tissue resident macrophages in health and cancer

“…During metastatic growth, AMs within the macrophage pool gradually get replaced by infiltrative macrophages, which may contribute to metastatic progression [ 57 ]. Mechanistically, the WNT/β-catenin/TNF-α pro-metastatic axis in AMs has been implicated, revealing potential therapeutic implications for targeting tumors that are resistant to the anti-neoplastic effects of TNF-α [ 58 ]. Moreover, targeting the recruitment of Monocytic-myeloid-derived suppressor cells (MO-MDSC) through CXCL10/CXCR3 and TLR4/CCL12 axis in AMs holds promise as a therapeutic strategy to suppress lung metastasis [ 59 ] (Fig.…”