ArticleClinical cancer research : an official journal of the American Association for Cancer Research2024
TAK1 Promotes an Immunosuppressive Tumor Microenvironment through Cancer-Associated Fibroblast Phenotypic Conversion in Pancreatic Ductal Adenocarcinoma.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed.
- Covalent FAPI Imaging-Guided Precision Surgery in Patients with Medullary Thyroid Carcinoma: A Phase II Clinical Trial.Clinical cancer research : an official journal of the American Association for Cancer Research · 2026Trial
- Blockade of Tumor TAK1 Induces DNA Damage and Immunogenic cGAS-STING Pathway Activation in Pancreatic Cancer.Gastroenterology · 2026Article
- Single-cell analysis reveals an endothelial TP53-CXCL14 axis in breast cancer progression.Journal of translational medicine · 2026Article
- Fluorescently engineered KRAS-mutant organoids as versatile tools for in vitro and in vivo cancer modeling.Biochemistry and biophysics reports · 2026Article
- A novel combination for in vivo breast cancer treatment: TAK1 inhibition combined with metformin and Lentinula edodes compounds synergistically reinvigorates CD8Journal of translational medicine · 2026Article
- Subtype-Independent Activation of NF-κB Signaling in Breast Cancer.International journal of molecular sciences · 2026Article
- The research advances of crosstalk between cancer-associated fibroblasts and tumor cells using co-culture organoids.Cell death & disease · 2026Review
- Charge-flip nanoparticles loaded with TAK1 inhibitors inhibit retinal neovascularization.Journal of nanobiotechnology · 2026Article
- Mitochondrial niches of residual disease in EGFR-mutant NSCLC: immune-constrained persistence and therapeutic interception.Frontiers in immunology · 2026Review
- NG25 Enhances Anti-Tumor Immunity inOncoTargets and therapy · 2026Article
- Cancer-associated fibroblasts as a potential therapeutic target for thyroid cancers.International journal of surgery (London, England) · 2026Review
- Cancer-Associated Fibroblasts: Origin, Classification, Tumorigenicity, and Targeting for Cancer Therapy.MedComm · 2025Review
- Metabolic and immune crosstalk between cancer-associated fibroblasts and pancreatic cancer cells.Journal of translational medicine · 2025Review
- Emerging role of cancer-associated fibroblasts in the premetastatic niche.Molecular cancer · 2025Review
- Unraveling tumor cell‑tumor microenvironment crosstalk through antibody array technologies (Review).International journal of oncology · 2025Review
- The 3D Language of Cancer: Communication via Extracellular Vesicles from Tumor Spheroids and Organoids.International journal of molecular sciences · 2025Review
- Association of α-SMA/FAP-positive cancer-associated fibroblasts with clinicopathological features and prognosis in extrahepatic cholangiocarcinoma.Diagnostic pathology · 2025Article
- Applications and challenges of patient-derived organoids in hepatobiliary and pancreatic cancers.World journal of gastroenterology · 2025Review
- Tumor organoid-immune co-culture models: exploring a new perspective of tumor immunity.Cell death discovery · 2025Review
- Cancer associated fibroblasts in cancer development and therapy.Journal of hematology & oncology · 2025Review
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12 authors.
Funding
Abstract
purposeWe aim to clarify the precise function of TGFβ1-activated kinase 1 (TAK1) in cancer-associated fibroblasts (CAF) within human pancreatic ductal adenocarcinoma (PDAC) by investigating its role in cytokine-mediated signaling pathways. EXPERIMENTAL
designThe expression of TAK1 in pancreatic cancer was confirmed by The Cancer Genome Atlas data and human pancreatic cancer specimens. CAFs from freshly resected PDAC specimens were cultured and used in a three-dimensional model for direct and indirect coculture with PDAC tumors to investigate TAK1 function. Additionally, organoids from [LSL-KrasG12D/+, LSL-Trp53R172H/+, Pdx1-Cre (KPC)] mice were mixed with CAFs and injected subcutaneously into C57BL/6 mice to explore in vivo functional interactions of TAK1.
resultsThe Cancer Genome Atlas data revealed significant upregulation of TAK1 in PDAC, associating with a positive correlation with the T-cell exhaustion signature. Knockdown of TAK1 in CAFs decreased the inflammatory CAF signature and increased the myofibroblastic CAF signature both in vitro and in vivo. The absence of TAK1 hindered CAF proliferation, blocked several inflammatory factors via multiple pathways associated with immunosuppression, and hindered epithelial-mesenchymal transition and outgrowth in vitro in spheroid cocultures with PDAC cells. Additionally, TAK1 inhibitor restrained tumor growth, increased CD4+ and CD8+ T-cell abundance, and reduced immunosuppressive cells present in vivo.
conclusionsBlocking the TAK1+ CAF phenotype leads to the conversion of protumorigenic CAFs to antitumorigenic CAFs. This highlights TAK1 as a potential therapeutic target, particularly in CAFs, and represents a novel avenue for combined immunotherapy in PDAC.
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