Journal
CELL REPORTS MEDICINE
Volume 3, Issue 6, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.xcrm.2022.100541
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Funding
- Common Fund of the Office of the Director of the National Institutes of Health
- NCI
- NHGRI
- NHLBI
- NIDA
- NIMH
- NINDS
- Medical Research Council UK Clinician Scientist Fellowship [G1002565, 99762]
- Cancer Research UK & Royal College of Surgeons of England Advanced Clinician Scientist Fellowship [A23924]
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This study reveals that cancer-associated fibroblasts (CAFs) drive chemotherapy resistance in esophageal adenocarcinomas (EACs) and can be targeted with phosphodiesterase type 5 inhibitors (PDE5i) to enhance chemotherapy efficacy.
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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