| Autor: |
Benjamin P. Sharpe, Annette Hayden, Antigoni Manousopoulou, Andrew Cowie, Robert C. Walker, Jack Harrington, Fereshteh 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 |
| Jazyk: |
angličtina |
| Rok vydání: |
2022 |
| Předmět: |
|
| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
|
