Evidence map›Paper›PMID 40833415›Full record

ArticleProceedings of the National Academy of Sciences of the United States of America2025

Macrophage TBK1 signaling drives the development and outgrowth of breast cancer brain metastasis.

Fatima Khan, Yang Liu, Donovan Whitfield, Lizhi Pang, Heba Ali, Yuyun Huang, Fei Zhou, Robert S Hagan, Katie Frenis, R Grant Rowe and 1 more

RetractedAbstract readRetracted Publication
In one paragraph

Article in Proceedings of the National Academy of Sciences of the United States of America, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It has been retracted, and should not be counted. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

  1. Article
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

11 authors.

Fatima KhanDepartment of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195.ORCID 0000-0002-8860-0339
Yang LiuDepartment of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195.ORCID 0009-0003-6585-0145
Donovan WhitfieldDepartment of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195.ORCID 0009-0006-7810-3482
Lizhi PangDepartment of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195.ORCID 0000-0002-7331-7514
Heba AliDepartment of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
Yuyun HuangDepartment of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195.ORCID 0009-0001-4137-3845
Fei ZhouDepartment of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195.ORCID 0000-0002-3334-100X
Robert S HaganDivision of Pulmonary Diseases and Critical Care Medicine, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.
Katie FrenisDepartment of Hematology, Boston Children's Hospital, Boston, MA 02115.
R Grant RoweDepartment of Hematology, Boston Children's Hospital, Boston, MA 02115.
Peiwen ChenDepartment of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195.ORCID 0000-0002-8129-9328

Funding

TUMOR METABOLISM PROGRAMP30CA043703 · NCI · CASE WESTERN RESERVE UNIVERSITY · PI Amar Desai · 1987 to 2026
$142.3M
Mechanism and therapeutic potential of microglia regulation in glioblastomaR01NS124594 · NINDS · NORTHWESTERN UNIVERSITY AT CHICAGO · PI Peiwen Chen · 2022 to 2026
$2.0M
Targeting macrophage reprogramming in glioblastomaR01NS127824 · NINDS · NORTHWESTERN UNIVERSITY AT CHICAGO · PI Peiwen Chen · 2023 to 2026
$1.6M
HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS) R01NS127824HHS | NIH | NCI | Center for Cancer Research (CCR) P30CA043703NCI NIH HHS P30 CA043703NINDS NIH HHS R01 NS124594NINDS NIH HHS R01 NS127824U.S. Department of Defense (DOD) W81XWH-21-1-0380
6 · The paper itself

Abstract

Tumor-associated macrophages (TAMs) are the predominant immune cells in the tumor microenvironment that promote breast cancer brain metastasis (BCBM). Here, we identify TANK-binding kinase (TBK1) as a critical signaling molecule enriched and activated in TAMs of BCBM tumors, playing an indispensable role in BCBM development and metastatic outgrowth in the brain. Mechanistically, BCBM cell-secreted matrix metalloproteinase 1 binds to protease-activated receptor 1 and integrin αVβ5 on macrophages, leading to TBK1 activation mediated by the nuclear factor-kappa B pathway. Reciprocally, TBK1-regulated TAMs produce granulocyte-macrophage colony-stimulating factor (GM-CSF) to drive breast cancer cell epithelial-mesenchymal transition, migration, and invasion, ultimately contributing to BCBM development and brain metastatic outgrowth. Inhibition of TBK1 signaling in TAMs or GM-CSF receptor in cancer cells impedes BCBM development and brain metastatic outgrowth. Correspondingly, the TBK1-GM-CSF signaling axis correlates with lower overall survival in patients with BCBM. Thus, TBK1-mediated tumor-TAM symbiotic interaction provides a promising therapeutic target for patients with BCBM.

Indexed as

Brain NeoplasmsBreast NeoplasmsMacrophagesProtein Serine-Threonine KinasesSignal TransductionTumor-Associated MacrophagesAnimalsCell Line, TumorCell MovementEpithelial-Mesenchymal TransitionFemaleGranulocyte-Macrophage Colony-Stimulating FactorHumansMiceNF-kappa BTumor MicroenvironmentGranulocyte-Macrophage Colony-Stimulating FactorNF-kappa BProtein Serine-Threonine KinasesTBK1 protein, humanbrain metastasisbreast cancerGM-CSFmacrophagesTBK1

Identifiers

PMID40833415
PMCPMC12403136

What OpenQuestion holds

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Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.