ArticleCellular & molecular immunology2024
BAG6 restricts pancreatic cancer progression by suppressing the release of IL33-presenting extracellular vesicles and the activation of mast cells.
Article in Cellular & molecular immunology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed.
- Mapping the functional dark proteome in cancer.Nature reviews. Cancer · 2026Review
- Screening and Engineering of Hetero-Bivalent Nanobody Targeting Interleukin-33 with Enhanced Binding Stability.Biomolecules · 2026Article
- Engineered cell-biomimetic nanosystems for anti-inflammatory therapy: Targeting, neutralization and immunomodulation.Acta pharmaceutica Sinica. B · 2026Review
- Endothelial-derived PANoptosis factor IL33 is a potential immunotherapy in breast cancer.iScience · 2026Article
- Gut microbiota and pancreatic cancer: tumorigenesis, progression, and clinical applications.Cancer biology & medicine · 2026Review
- Long-term cytokine exposure remodels the methylome and transcriptome of recessive dystrophic epidermolysis bullosa keratinocytes - a bioinformatic analysis.Frontiers in cell and developmental biology · 2026Article
- Challenges and caveats in manipulating extracellular vesicle secretion from pancreatic cancer cells.Cancer biology & therapy · 2025Article
- Special Issue "Molecular Mechanisms of Allergy and Asthma: 3rd Edition".International journal of molecular sciences · 2025Article
- Targeting Mast Cell Activation and MIF-Mediated Remodelling Enhances Chemotherapy Response in Pancreatic Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Article
- Unlocking IL-33: New Insights into Tumor Immunity.Immune network · 2025Review
- Neutrophil membrane-camouflaged SiRNA nanoplatform targeting IL-33 attenuates osteoarthritis through autophagy-dependent senescence regulation.Journal of nanobiotechnology · 2025Article
- Plasticity and Functional Heterogeneity of Cancer-Associated Fibroblasts.Cancer research · 2025Review
- HSP70 is a chaperone for IL-33 activity in chronic airway disease.JCI insight · 2025Article
- The Crosstalk with CXCL10-Rich Tumor-Associated Mast Cells Fuels Pancreatic Cancer Progression and Immune Escape.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Cancer-Associated Fibroblasts as the "Architect" of the Lung Cancer Immune Microenvironment: Multidimensional Roles and Synergistic Regulation with Radiotherapy.International journal of molecular sciences · 2025Review
- Prognostic implications and characterization of tumor-associated tertiary lymphoid structures genes in pancreatic cancer.Journal of translational medicine · 2025Article
- Mast cells: key players in digestive system tumors and their interactions with immune cells.Cell death discovery · 2025Review
- Mast Cells in the Solid Tumor Microenvironment: Multiple Roles and Targeted Therapeutic Potential.Oncology research · 2025Review
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Authors and funding
28 authors.
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Abstract
Recent studies reveal a critical role of tumor cell-released extracellular vesicles (EVs) in pancreatic cancer (PC) progression. However, driver genes that direct EV function, the EV-recipient cells, and their cellular response to EV uptake remain to be identified. Therefore, we studied the role of Bcl-2-associated-anthanogene 6 (BAG6), a regulator of EV biogenesis for cancer progression. We used a Cre recombinase/LoxP-based reporter system in combination with single-cell RNA sequencing to monitor in vivo EV uptake and tumor microenvironment (TME) changes in mouse models for pancreatic ductal adenocarcinoma (PDAC) in a Bag6 pro- or deficient background. In vivo data were validated using mouse and human organoids and patient samples. Our data demonstrated that Bag6-deficient subcutaneous and orthotopic PDAC tumors accelerated tumor growth dependent on EV release. Mechanistically, this was attributed to mast cell (MC) activation via EV-associated IL33. Activated MCs promoted tumor cell proliferation and altered the composition of the TME affecting fibroblast polarization and immune cell infiltration. Tumor cell proliferation and fibroblast polarization were mediated via the MC secretome containing high levels of PDGF and CD73. Patients with high BAG6 gene expression and high protein plasma level have a longer overall survival indicating clinical relevance. The current study revealed a so far unknown tumor-suppressing activity of BAG6 in PDAC. Bag6-deficiency allowed the release of EV-associated IL33 which modulate the TME via MC activation promoting aggressive tumor growth. MC depletion using imatinib diminished tumor growth providing a scientific rationale to consider imatinib for patients stratified with low BAG6 expression and high MC infiltration. EVs derived from BAG6-deficient pancreatic cancer cells induce MC activation via IL33/Il1rl1. The secretome of activated MCs induces tumor proliferation and changes in the TME, particularly shifting fibroblasts into an inflammatory cancer-associated fibroblast (iCAF) phenotype. Blocking EVs or depleting MCs restricts tumor growth.
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