Phosphodiesterase type 5 inhibitors enhance chemotherapy in preclinical models of esophageal adenocarcinoma by targeting cancer-associated fibroblasts

Sharpe, Benjamin P.; Hayden, Annette; Manousopoulou, Antigoni; Cowie, Andrew; Walker, Robert C.; Harrington, Jack; Izadi, Fereshteh; Breininger, Stella P.; Gibson, Jane; Pickering, Oliver; Jaynes, Eleanor; Kyle, Ewan; Saunders, John H.; Parsons, Simon L.; Ritchie, Alison A.; Clarke, Philip A.; Collier, Pamela; Mongan, Nigel P.; Bates, David O.; Yacqub-Usman, Kiren; Garbis, Spiros D.; Walters, Zoë; Rose-Zerilli, Matthew; Grabowska, Anna M.; Underwood, Timothy J.

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.

Citation

Sharpe, B. P., Hayden, A., Manousopoulou, A., Cowie, A., Walker, R. C., Harrington, J., …Underwood, T. J. (2022). Phosphodiesterase type 5 inhibitors enhance chemotherapy in preclinical models of esophageal adenocarcinoma by targeting cancer-associated fibroblasts. Cell Reports Medicine, 3(6), Article 100541. https://doi.org/10.1016/j.xcrm.2022.100541

• Journal Article Type: Article
• Acceptance Date: Jan 28, 2022
• Online Publication Date: Jun 21, 2022
• Publication Date: Jun 21, 2022
• Deposit Date: Apr 9, 2023
• Publicly Available Date: May 26, 2023
• Journal: Cell Reports Medicine
• Print ISSN: 2666-3791
• Electronic ISSN: 2666-3791
• Publisher: Elsevier BV
• Peer Reviewed: Peer Reviewed
• Volume: 3
• Issue: 6
• Article Number: 100541
• DOI: https://doi.org/10.1016/j.xcrm.2022.100541
• Keywords: General Biochemistry, Genetics and Molecular Biology
• Public URL: https://nottingham-repository.worktribe.com/output/8636582
• Publisher URL: https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(22)00041-6?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2666379122000416%3Fshowall%3Dtrue
• Additional Information: This article is maintained by: Elsevier; Article Title: Phosphodiesterase type 5 inhibitors enhance chemotherapy in preclinical models of esophageal adenocarcinoma by targeting cancer-associated fibroblasts; Journal Title: Cell Reports Medicine; CrossRef DOI link to publisher maintained version: https://doi.org/10.1016/j.xcrm.2022.100541; Content Type: article; Copyright: © 2022 The Authors.