{"doi":"10.1172/jci.insight.160978","title":"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.","journal":"JCI Insight","year":2023,"id":331321,"datarank":0.5101796072493234,"base_score":3.4011973816621555,"endowment":3.4011973816621555,"self_citation_contribution":0.5101796072493234,"citation_network_contribution":0.0,"self_endowment_contribution":0.5101796072493234,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":29,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9548,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":442061,"name":"Stephanie L. Tzetzo","orcid":"0000-0002-4088-6331","position":1,"is_corresponding":false},{"id":413118,"name":"Sean Colligan","orcid":"0000-0003-0151-5869","position":2,"is_corresponding":false},{"id":1056730,"name":"Mary L. Hensen","orcid":null,"position":3,"is_corresponding":false},{"id":397564,"name":"Craig M. Brackett","orcid":"0000-0001-9897-5276","position":4,"is_corresponding":false},{"id":934809,"name":"Björn E. Clausen","orcid":"0000-0002-2484-7842","position":5,"is_corresponding":false},{"id":32746,"name":"Makoto M. Taketo","orcid":"0000-0002-9032-4505","position":6,"is_corresponding":false},{"id":265642,"name":"Scott I. Abrams","orcid":null,"position":7,"is_corresponding":false},{"id":350462,"name":"Elliot D. Kramer","orcid":"0000-0002-2749-8158","position":0,"is_corresponding":true}],"reference_count":80,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:09:19.317824Z","pmid":"37092550","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}