ArticleCell death & disease2020
Stroma secreted IL6 selects for "stem-like" population and alters pancreatic tumor microenvironment by reprogramming metabolic pathways.
Article in Cell death & disease, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 42 citations in OpenAlex.
- Article
- M2-polarized tumor-associated macrophages as key orchestrators of gastric cancer pathogenesis and therapeutic resistance.Discover oncology · 2026Review
- Heterocellular crosstalk and architecture of the pancreatic tumour microenvironment.Nature reviews. Cancer · 2026Review
- Mitochondrial metabolism in cancer stem cells (CSCs): molecular and diagnostic implications.Frontiers in molecular biosciences · 2026Review
- Dynamic feedback between IL-6 and TWIST1 drives pancreatic cancer progression.Translational gastroenterology and hepatology · 2026Article
- Cytokine-mediated regulation of immune cell metabolic pathways in the tumor microenvironment.Naunyn-Schmiedeberg's archives of pharmacology · 2025Review
- The double-edged sword: impact of antibiotic use on immunotherapy efficacy in advanced hepatocellular carcinoma.BMC gastroenterology · 2025Article
- The multi-faceted roles of cancer-associated fibroblasts in pancreatic cancer.Cellular signalling · 2025Review
- Lactate-mediated metabolic reprogramming of tumor-associated macrophages: implications for tumor progression and therapeutic potential.Frontiers in immunology · 2025Review
- Lactylation in digestive system tumors: from mechanisms to therapeutic target.Frontiers in oncology · 2025Review
- Role of Interleukins in Pancreatic Cancer: A Literature Review.Journal of gastrointestinal cancer · 2024Review
- Fibroblast subtypes in pancreatic cancer and pancreatitis: from mechanisms to therapeutic strategies.Cellular oncology (Dordrecht, Netherlands) · 2024Review
- Functional Roles of CD133: More than Stemness Associated Factor Regulated by the Microenvironment.Stem cell reviews and reports · 2024Review
- Research trends on immunotherapy for pancreatic cancer: A bibliometric analysis.Human vaccines & immunotherapeutics · 2023Article
- Stromal-Modulated Epithelial-to-Mesenchymal Transition in Cancer Cells.Biomolecules · 2023Review
- SALL4-related gene signature defines a specific stromal subset of pancreatic ductal adenocarcinoma with poor prognostic features.Molecular oncology · 2023Article
- The Metabolism and Immune Environment in Diffuse Large B-Cell Lymphoma.Metabolites · 2023Review
- Pancreatic cancer stemness: dynamic status in malignant progression.Journal of experimental & clinical cancer research : CR · 2023Review
- A Quick Guide to CAF Subtypes in Pancreatic Cancer.Cancers · 2023Review
- Review
Corrections and comments
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Authors and funding
11 authors at 2 institutions in 2 countries.
Funding
Abstract
Pancreatic adenocarcinoma is a devastating disease with an abysmal survival rate of 9%. A robust fibro-inflammatory and desmoplastic stroma, characteristic of pancreatic cancer, contribute to the challenges in developing viable therapeutic strategies in this disease. Apart from constricting blood vessels and preventing efficient drug delivery to the tumor, the stroma also contributes to the aggressive biology of cancer along with its immune-evasive microenvironment. In this study, we show that in pancreatic tumors, the developing stroma increases tumor initiation frequency in pancreatic cancer cells in vivo by enriching for CD133 + aggressive "stem-like" cells. Additionally, the stromal fibroblasts secrete IL6 as the major cytokine, increases glycolytic flux in the pancreatic tumor cells, and increases lactate efflux in the microenvironment via activation of the STAT signaling pathway. We also show that the secreted lactate favors activation of M2 macrophages in the tumor microenvironment, which excludes CD8 + T cells in the tumor. Our data additionally confirms that the treatment of pancreatic tumors with anti-IL6 antibody results in tumor regression as well as decreased CD133 + population within the tumor. Furthermore, inhibiting the lactate efflux in the microenvironment reduces M2 macrophages, and makes pancreatic tumors more responsive to anti-PD1 therapy. This suggests that stromal IL6 driven metabolic reprogramming plays a significant role in the development of an immune-evasive microenvironment. In conclusion, our study shows that targeting the metabolic pathways affected by stromal IL6 can make pancreatic tumors amenable to checkpoint inhibitor therapy.
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Registered trials
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.