Transcriptomics

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


ABSTRACT: The main cause of malignancy-related mortality is metastasis. While 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 (TME), especially macrophages. Recruited macrophages infiltrating the TME are correlated with worse outcomes, because they are rendered pro-tumorigenic through defined tumor-driven transcription factor-mediated programs. However, the pathways that govern the dysregulation of tissue-resident macrophages (TRMs) are less well understood. Alveolar macrophages (AMs) are a TRM population with critical roles in both 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 novel genetic β-catenin gain-of-function approach, we demonstrated that 1) enhanced β-catenin in AMs heightened lung metastasis; 2) β-catenin activity in AMs drove a dysregulated inflammatory program strongly associated with Tnf expression; and 3) localized TNF blockade abrogated this metastatic outcome. Lastly, CTNNB1 and TNF expression were positively correlated in AMs of lung cancer patients. Overall, our findings revealed a novel Wnt/β-catenin–TNF-α pro-metastatic axis in AMs with potential therapeutic implications against tumors refractory to TNF-α induced necrosis.

ORGANISM(S): Mus musculus

PROVIDER: GSE200508 | GEO | 2022/12/19

REPOSITORIES: GEO

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