ArticleCell reports. Medicine2022
Phosphodiesterase type 5 inhibitors enhance chemotherapy in preclinical models of esophageal adenocarcinoma by targeting cancer-associated fibroblasts.
Article in Cell reports. Medicine, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 24 citations in OpenAlex.
- Esophageal cancer: from pathogenesis to precision therapies.Signal transduction and targeted therapy · 2026Review
- The neoantigen and associated tumour microenvironment in long-term survivors with oesophageal adenocarcinoma.Frontiers in immunology · 2026Article
- Restoring dendritic cell interstitial motility via PDE5 inhibition for sustained antitumor immunity.Journal of the National Cancer Center · 2025Article
- The Interplay Between Esophageal Adenocarcinoma and Its Tumor Microenvironment: Toward Innovative Therapies.Cells · 2025Review
- Cancer-associated fibroblasts as mediators of tissue microenvironment remodeling in cancer.Current opinion in cell biology · 2025Review
- Cancer-associated fibroblasts are associated with neo-adjuvant treatment response in oesophageal adenocarcinoma.British journal of cancer · 2025Article
- Interactions between cancer-associated fibroblasts and the extracellular matrix in oesophageal cancer.Matrix biology : journal of the International Society for Matrix Biology · 2025Review
- Cancer network pharmacology: multi-network regulatory mechanisms and future directions.Medical oncology (Northwood, London, England) · 2025Review
- Phosphodiesterases: Evolving Concepts and Implications for Human Therapeutics.Annual review of pharmacology and toxicology · 2025Review
- PDE10A as a novel diagnostic and therapeutic target in cancer: insights and challenges.Frontiers in oncology · 2025Review
- Article
- Patient-derived tumor organoid and fibroblast assembloid models for interrogation of the tumor microenvironment in esophageal adenocarcinoma.Cell reports methods · 2024Article
- The role of the fibroblast in Barrett's esophagus and esophageal adenocarcinoma.Current opinion in gastroenterology · 2024Review
- Tumour microenvironment influences response to treatment in oesophageal adenocarcinoma.Frontiers in immunology · 2023Review
Corrections and comments
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Authors and funding
25 authors at 4 institutions in 2 countries.
Funding
Abstract
The chemotherapy resistance of esophageal adenocarcinomas (EACs) is underpinned by cancer cell extrinsic mechanisms of the tumor microenvironment (TME). We demonstrate that, by targeting the tumor-promoting functions of the predominant TME cell type, cancer-associated fibroblasts (CAFs) with phosphodiesterase type 5 inhibitors (PDE5i), we can enhance the efficacy of standard-of-care chemotherapy. In ex vivo conditions, PDE5i prevent the transdifferentiation of normal fibroblasts to CAF and abolish the tumor-promoting function of established EAC CAFs. Using shotgun proteomics and single-cell RNA-seq, we reveal PDE5i-specific regulation of pathways related to fibroblast activation and tumor promotion. Finally, we confirm the efficacy of PDE5i in combination with chemotherapy in close-to-patient and in vivo PDX-based model systems. These findings demonstrate that CAFs drive chemotherapy resistance in EACs and can be targeted by repurposing PDE5i, a safe and well-tolerated class of drug administered to millions of patients world-wide to treat erectile dysfunction.
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Registered trials
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