ArticleMatrix biology : journal of the International Society for Matrix Biology2022
Aberrant TIMP-1 overexpression in tumor-associated fibroblasts drives tumor progression through CD63 in lung adenocarcinoma.
Article in Matrix biology : journal of the International Society for Matrix Biology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 39 citations in OpenAlex.
- Spatial transcriptomics unveils the in situ cellular and molecular hallmarks of the lung in fatal COVID-19.Nature communications · 2026Article
- Cancer-associated fibroblasts in therapeutic resistance of hepatocellular carcinoma: evidence, mechanisms, and translational implications.Medical oncology (Northwood, London, England) · 2026Review
- Proteomic profiling of CD133 + and CD326 + (EpCAM) subpopulations in A549 cells: insights into pluripotency and tumor heterogeneity.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2026Article
- Construction of a ferroptosis-related prognostic signature and identification ofTranslational cancer research · 2026Article
- An epithelial mesenchymal transition associated gene signature stratifies risk of ulcerative colitis associated colorectal cancer.Discover oncology · 2026Article
- Proteolysis activity mapping and substrate discovery platform for identifying tumor-activated biosensors.Nature chemical biology · 2026Article
- Antagonistic SMAD2/3 control of TIMP-1, VEGF-A, and hypoxia signaling in myofibroblasts shapes histotype-specific angiogenesis in lung cancer.Cell death & disease · 2026Article
- A nanosystem targeting tissue inhibitor of metalloproteinase-1 for continuous spatiotemporal idiopathic pulmonary fibrosis therapy.Nature communications · 2026Article
- TIMP1 Derived from Mesenchymal Stem Cells Promotes Bladder Cancer Progression by Regulating the Formation of VDIMs through the RAP1 Pathway.International journal of biological sciences · 2026Article
- Integrin-Mediated TIMP1 Signaling Reprograms Liver Macrophages and Accelerates Colorectal Cancer Metastasis.Cells · 2025Article
- Stromagenesis and cancer-associated fibroblast heterogeneity in primary tumors and metastasis: focus in non-small cell lung cancer.FEBS open bio · 2025Review
- The role of tetraspanins in organ fibrosis: mechanisms and therapeutic perspectives.Journal of translational medicine · 2025Review
- SpaIM: single-cell spatial transcriptomics imputation via style transfer.Nature communications · 2025Article
- Hidden forces: the impact of cancer-associated fibroblasts on non-small cell lung cancer development and therapy.Journal of translational medicine · 2025Review
- Spatial transcriptomics of progression gene signature and tumor microenvironment leading to progression in mycosis fungoides.Blood advances · 2025Article
- MicroRNAs in Diffuse Large B-Cell Lymphoma (DLBCL): Biomarkers with Prognostic Potential.Cancers · 2025Article
- Integrated radiomics and immune infiltration analysis to decipher immunotherapy efficacy in lung adenocarcinoma.Quantitative imaging in medicine and surgery · 2025Article
- Tumor-associated-fibrosis and active collagen-CD44 axis characterize a poor-prognosis subtype of gastric cancer and contribute to tumor immunosuppression.Journal of translational medicine · 2025Article
- Prognostic value of metal-based ferroptosis and cuproptosis genes and score in lower grade gliomas.Frontiers in immunology · 2025Article
- Pair-matched analysis of Circulating Melanoma Cells (CMCs) before and after Immunotherapy in Relation to other Melanoma-Specific Biomarkers.Journal of Cancer · 2025Article
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Authors and funding
17 authors at 7 institutions in 2 countries.
Funding
Abstract
Tissue inhibitor of metalloproteinase-1 (TIMP-1) is an important regulator of extracellular matrix turnover that has been traditionally regarded as a potential tumor suppressor owing to its inhibitory effects of matrix metalloproteinases. Intriguingly, this interpretation has been challenged by the consistent observation that increased expression of TIMP-1 is associated with poor prognosis in virtually all cancer types including lung cancer, supporting a tumor-promoting function. However, how TIMP-1 is dysregulated within the tumor microenvironment and how it drives tumor progression in lung cancer is poorly understood. We analyzed the expression of TIMP-1 and its cell surface receptor CD63 in two major lung cancer subtypes: lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC), and defined the tumor-promoting effects of their interaction. We found that TIMP-1 is aberrantly overexpressed in tumor-associated fibroblasts (TAFs) in ADC compared to SCC. Mechanistically, TIMP-1 overexpression was mediated by the selective hyperactivity of the pro-fibrotic TGF-β1/SMAD3 pathway in ADC-TAFs. Likewise, CD63 was upregulated in ADC compared to SCC cells. Genetic analyses revealed that TIMP-1 secreted by TGF-β1-activated ADC-TAFs is both necessary and sufficient to enhance growth and invasion of ADC cancer cells in culture, and that tumor cell expression of CD63 was required for these effects. Consistently, in vivo analyses revealed that ADC cells co-injected with fibroblasts with reduced SMAD3 or TIMP-1 expression into immunocompromised mice attenuated tumor aggressiveness compared to tumors bearing parental fibroblasts. We also found that high TIMP1 and CD63 mRNA levels combined define a stronger prognostic biomarker than TIMP1 alone. Our results identify an excessive stromal TIMP-1 within the tumor microenvironment selectively in lung ADC, and implicate it in a novel tumor-promoting TAF-carcinoma crosstalk, thereby pointing to TIMP-1/CD63 interaction as a novel therapeutic target in lung cancer.
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