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., Izadi, F., Breininger, S. P., Gibson, J., Pickering, O., Jaynes, E., Kyle, E., Saunders, J. H., Parsons, S. L., Ritchie, A. A., Clarke, P. A., Collier, P., Mongan, N. P., Bates, D. O., Yacqub-Usman, K., …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: Cell Press
• 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.