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Modulation of the tumour promoting functions of cancer associated fibroblasts by phosphodiesterase type 5 inhibition increases the efficacy of chemotherapy in human preclinical models of esophageal adenocarcinoma

Hayden, Annette and Manousopoulou, Antigoni and Cowie, Andrew and Walker, Robert and Sharpe, Benjamin P. and Harrington, Jack and Izadi, Fereshteh and Kyle, Ewan and Saunders, John H. and Parsons, Simon L. and Ritchie, Alison A. and Clarke, Philip A. and Collier, Pamela and Garbis, Spiros D. and Rose-Zerilli, Matthew and Grabowska, Anna M. and Underwood, Timothy J. (2020) Modulation of the tumour promoting functions of cancer associated fibroblasts by phosphodiesterase type 5 inhibition increases the efficacy of chemotherapy in human preclinical models of esophageal adenocarcinoma. . (Unpublished) https://resolver.caltech.edu/CaltechAUTHORS:20200423-120949690

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Abstract

Background and aims: Esophageal adenocarcinoma (EAC) is chemoresistant in the majority of cases. The tumor-promoting biology of cancer associated fibroblasts (CAF) make them a target for novel therapies. Phosphodiesterase type 5 inhibitors (PDE5i) have been shown to regulate the activated fibroblast phenotype in benign disease. We investigated the potential for CAF modulation in EAC using PDE5i to enhance the efficacy of chemotherapy. Methods: EAC fibroblasts were treated with PDE5i and phenotypic effects examined using immunoblotting, immunohistochemistry, gel contraction, transwell invasion, organotypics, single cell RNAseq and shotgun proteomics. The combination of PDE5i with standard-of-care chemotherapy (Epirubicin, 5-Fluorouracil and Cisplatin) was tested for safety and efficacy in validated near-patient model systems (3D tumor growth assays (3D-TGAs) and patient derived xenograft (PDX) mouse models). Results: PDE5i treatment reduced alpha-SMA expression in CAFs by 50% (p<0.05), associated with a significant reduction in the ability of CAFs to contract collagen-1 gels and induce cancer cell invasion, (p<0.05). RNAseq and proteomic analysis of CAF and EAC cell lines revealed PDE5i specific regulation of pathways related to fibroblast activation and tumor promotion. 3D-TGA assays confirmed the importance of stromal cells to chemoresistance in EAC, which could be attenuated by PDE5i. Chemotherapy+PDE5i in PDX-bearing mice was safe and significantly reduced PDX tumor volume (p<0.05). Conclusion: PDE5 is a candidate for clinical trials to alter the fibroblast phenotype in esophageal cancer. We demonstrate the specificity of PDE5i for fibroblasts to prevent transdifferentiation and revert the CAF phenotype. Finally, we confirm the efficacy of PDE5i in combination with chemotherapy in close-to-patient in vitro and in vivo PDX-based model systems.


Item Type:Report or Paper (Discussion Paper)
Related URLs:
URLURL TypeDescription
https://doi.org/10.1101/2020.04.21.052647DOIDiscussion Paper
ORCID:
AuthorORCID
Manousopoulou, Antigoni0000-0001-5028-1865
Sharpe, Benjamin P.0000-0002-7594-1601
Harrington, Jack0000-0003-2926-1223
Garbis, Spiros D.0000-0002-1050-0805
Rose-Zerilli, Matthew0000-0002-1064-5350
Underwood, Timothy J.0000-0001-9455-2188
Additional Information:The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. Posted April 23, 2020. Funding: Medical Research Council UK Clinician Scientist Fellowship to T.J.U. "Exploring stromalepithelial 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. Author contribution: A.H. performed experiments, interpreted results, conducted analysis and wrote manuscript; A.M. performed experiments, interpreted results and wrote manuscript; A.C. performed experiments, interpreted results and wrote manuscript; R.W. performed experiments, interpreted results and wrote manuscript; B.P.S. interpreted results and edited manuscript; J.H. performed experiments; F.I. performed bioinformatic analysis and interpreted results; E.K. performed experiments; J.H.S., S.P., A.A.R., P.A.C and P.C. performed experiments, interpreted results, and wrote manuscript; S.D.G. performed experiments, interpreted results and wrote manuscript; M.R.Z. performed experiments, interpreted results and wrote manuscript; A.G. designed study, interpreted results, and wrote manuscript; T.J.U. raised funding, designed study, performed experiments, interpreted results and wrote manuscript. All authors revised the manuscript and approved the final version. The authors declare no conflict of interest.
Funders:
Funding AgencyGrant Number
Medical Research Council (UK)G1002565
Cancer Research UKUNSPECIFIED
Royal College of Surgeons of EnglandA23924
Subject Keywords:Esophageal adenocarcinoma (EAC), cancer associated fibroblast (CAFs), phosphodiesterase type 5 inhibitors (PDE5i)
Record Number:CaltechAUTHORS:20200423-120949690
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20200423-120949690
Official Citation:Modulation of the tumour promoting functions of cancer associated fibroblasts by phosphodiesterase type 5 inhibition increases the efficacy of chemotherapy in human preclinical models of esophageal adenocarcinoma. Annette Hayden, Antigoni Manousopoulou, Andrew Cowie, Robert Walker, Benjamin P Sharpe, Jack Harrington, Fereshteh Izadi, Ewan Kyle, John H. Saunders, Simon L. Parsons, Alison A. Ritchie, Philip A. Clarke, Pamela Collier, Spiros D. Garbis, Matthew Rose-Zerilli, Anna M. Grabowska, Timothy J. Underwood. bioRxiv 2020.04.21.052647; doi: https://doi.org/10.1101/2020.04.21.052647
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:102750
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:23 Apr 2020 20:42
Last Modified:09 Apr 2021 20:44

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