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Phosphodiesterase type 5 inhibitors enhance chemotherapy in preclinical models of esophageal adenocarcinoma by targeting cancer-associated fibroblasts
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Annette Hayden,
Antigoni Manousopoulou,
Andrew Cowie,
Robert C. Walker ,
Jack Harrington,
Angel Izadi,
Stella P. Breininger ,
Jane Gibson,
Oliver Pickering,
Eleanor Jaynes,
Ewan Kyle ,
John H. Saunders ,
Simon L. Parsons,
Alison A. Ritchie ,
Philip A. Clarke,
Pamela Collier,
Nigel P. Mongan,
David O. Bates,
Kiren Yacqub-Usman,
Spiros D. Garbis,
Zoë Walters,
Matthew Rose-Zerilli,
Anna M. Grabowska ,
Timothy J. Underwood
Cell Reports Medicine, Volume: 3, Issue: 6, Start page: 100541
Swansea University Author: Angel Izadi
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Copyright: 2022 The Authors. This is an open access article under the CC BY license.
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DOI (Published version): 10.1016/j.xcrm.2022.100541
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 phospho...
| Published in: | Cell Reports Medicine |
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| ISSN: | 2666-3791 2666-3791 |
| Published: |
Elsevier BV
2022
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| Online Access: |
Check full text
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| URI: | https://cronfa.swan.ac.uk/Record/cronfa60404 |
| 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. [Abstract copyright: Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.] |
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| Keywords: |
esophageal adenocarcinoma; cancer-associated fibroblasts; phosphodiesterase type 5 inhibitors; chemotherapy; preclinical models |
| College: |
Faculty of Medicine, Health and Life Sciences |
| Funders: |
Medical Research Council UK Clinician Scientist Fellowship to T.J.U. ‘‘Exploring stromal-epithelial interactions in oesophageal cancer’’ G1002565 IDN0. 99762; Cancer Research UK & Royal College of Surgeons of England Advanced Clinician Scientist Fellowship to T.J.U. ‘‘Cellular interplay in oesophageal cancer.’’ A23924. |
| Issue: |
6 |
| Start Page: |
100541 |