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

Benjamin P. Sharpe Orcid Logo, Annette Hayden, Antigoni Manousopoulou, Andrew Cowie, Robert C. Walker Orcid Logo, Jack Harrington, Angel Izadi, Stella P. Breininger Orcid Logo, Jane Gibson, Oliver Pickering, Eleanor Jaynes, Ewan Kyle Orcid Logo, John H. Saunders Orcid Logo, Simon L. Parsons, Alison A. Ritchie Orcid Logo, 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 Orcid Logo, Timothy J. Underwood Orcid Logo

Cell Reports Medicine, Volume: 3, Issue: 6, Start page: 100541

Swansea University Author: Angel Izadi

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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...

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Published in: Cell Reports Medicine
ISSN: 2666-3791 2666-3791
Published: Elsevier BV 2022
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URI: https://cronfa.swan.ac.uk/Record/cronfa60404
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spelling 2022-07-07T17:17:32.5050727 v2 60404 2022-07-07 Phosphodiesterase type 5 inhibitors enhance chemotherapy in preclinical models of esophageal adenocarcinoma by targeting cancer-associated fibroblasts 446db7a27e7474eb533e7e4795f97721 Angel Izadi Angel Izadi true false 2022-07-07 BMS 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.] Journal Article Cell Reports Medicine 3 6 100541 Elsevier BV 2666-3791 2666-3791 esophageal adenocarcinoma; cancer-associated fibroblasts; phosphodiesterase type 5 inhibitors; chemotherapy; preclinical models 21 6 2022 2022-06-21 10.1016/j.xcrm.2022.100541 COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University 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. 2022-07-07T17:17:32.5050727 2022-07-07T17:05:02.5162734 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Benjamin P. Sharpe 0000-0002-7594-1601 1 Annette Hayden 2 Antigoni Manousopoulou 3 Andrew Cowie 4 Robert C. Walker 0000-0003-2101-1318 5 Jack Harrington 6 Angel Izadi 7 Stella P. Breininger 0000-0003-2046-3187 8 Jane Gibson 9 Oliver Pickering 10 Eleanor Jaynes 11 Ewan Kyle 0000-0002-3352-6274 12 John H. Saunders 0000-0003-0383-3676 13 Simon L. Parsons 14 Alison A. Ritchie 0000-0002-5092-4979 15 Philip A. Clarke 16 Pamela Collier 17 Nigel P. Mongan 18 David O. Bates 19 Kiren Yacqub-Usman 20 Spiros D. Garbis 21 Zoë Walters 22 Matthew Rose-Zerilli 23 Anna M. Grabowska 0000-0003-1507-921x 24 Timothy J. Underwood 0000-0001-9455-2188 25 60404__24492__25828aca726243bd8ebef436e97463bc.pdf 60404_VoR.pdf 2022-07-07T17:14:52.5976536 Output 5404951 application/pdf Version of Record true Copyright: 2022 The Authors. This is an open access article under the CC BY license. true eng http://creativecommons.org/licenses/by/4.0/
title Phosphodiesterase type 5 inhibitors enhance chemotherapy in preclinical models of esophageal adenocarcinoma by targeting cancer-associated fibroblasts
spellingShingle Phosphodiesterase type 5 inhibitors enhance chemotherapy in preclinical models of esophageal adenocarcinoma by targeting cancer-associated fibroblasts
Angel Izadi
title_short Phosphodiesterase type 5 inhibitors enhance chemotherapy in preclinical models of esophageal adenocarcinoma by targeting cancer-associated fibroblasts
title_full Phosphodiesterase type 5 inhibitors enhance chemotherapy in preclinical models of esophageal adenocarcinoma by targeting cancer-associated fibroblasts
title_fullStr Phosphodiesterase type 5 inhibitors enhance chemotherapy in preclinical models of esophageal adenocarcinoma by targeting cancer-associated fibroblasts
title_full_unstemmed Phosphodiesterase type 5 inhibitors enhance chemotherapy in preclinical models of esophageal adenocarcinoma by targeting cancer-associated fibroblasts
title_sort Phosphodiesterase type 5 inhibitors enhance chemotherapy in preclinical models of esophageal adenocarcinoma by targeting cancer-associated fibroblasts
author_id_str_mv 446db7a27e7474eb533e7e4795f97721
author_id_fullname_str_mv 446db7a27e7474eb533e7e4795f97721_***_Angel Izadi
author Angel Izadi
author2 Benjamin P. Sharpe
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
format Journal article
container_title Cell Reports Medicine
container_volume 3
container_issue 6
container_start_page 100541
publishDate 2022
institution Swansea University
issn 2666-3791
2666-3791
doi_str_mv 10.1016/j.xcrm.2022.100541
publisher Elsevier BV
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
document_store_str 1
active_str 0
description 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.]
published_date 2022-06-21T04:18:29Z
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