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

Sharpe, Benjamin; Hayden, Annette; Manousopoulou, Antigoni; Cowie, Andrew; Walker, Robert; Harrington, Jack; Izadi, Fereshteh; Breininger, Stella P.; Gibson, Jane; Pickering, Oliver; Jaynes, Eleanor; Kyle, Ewan; Saunders, J.; Parsons, Simon L.; Ritchie, Alison; Clarke, Philip; Collier, Pamela; Mongan, Nigel P.; Bates, David O.; Yacqub-Usman, Kiren; Garbis, Spiros D.; Walters, Zoë S.; Rose-Zerilli, Matthew; Grabowska, Anna; Underwood, Tim

doi:10.1016/j.xcrm.2022.100541

Cited by 8 publications

(9 citation statements)

References 75 publications

(124 reference statements)

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“…Patient 191 had lower levels of CK7 expression and the OESO-191 assembloid contained an admixture of CK7+ and CK20+ tumor cells. Next, we examined the expression of myofibroblast CAF markers α-SMA and POSTN as these are known to be associated with poor prognosis in EAC 8,11 . Assembloids containing OESO-005 and OESO-191 grown with CAF1412 produced an SMA-negative and POSTN-low stromal microenvironment (Figure 2D), whereas the stromal microenvironment of OESO-195 grown with CAF669 produced a stromal microenvironment with SMA-positive cells distributed throughout, suggesting some myofibroblast CAF differentiation in this model.…”

Section: Pdo-caf Assembloids Recapitulate Features Of Primary Tumorsmentioning

confidence: 99%

“…We have previously shown that markers of myofibroblast CAF differentiation, α-smooth muscle actin (α-SMA) and periostin (POSTN) are associated with poor prognosis in EAC 8 . Targeting myofibroblast differentiation in EAC CAFs can be achieved in preclinical models using PDE5 inhibitors and sensitizes tumor cells to chemotherapy 11 . These studies highlight the importance of the EAC TME in governing tumor behavior, and the TME must be considered when studying drug sensitivity, which current EAC models are lacking 12 .…”

Section: Introductionmentioning

confidence: 99%

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Patient-Derived Tumor Organoid and Fibroblast Assembloid Models for interrogation of the tumor microenvironment in Esophageal Adenocarcinoma

Sharpe,

Nazlamova,

Tse

et al. 2024

Preprint

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The tumor microenvironment (TME) comprises all non-tumor elements of cancer and strongly influences disease progression and phenotype. To understand tumor biology and accurately test new therapeutic strategies, representative models should contain both tumor cells and normal cells of the TME. Here we describe and characterize co-culture tumor-derived organoids and cancer-associated fibroblasts (CAFs), a major component of the TME, in matrix-embedded assembloid models of esophageal adenocarcinoma (EAC). We demonstrate that the assembloid models faithfully recapitulate the differentiation status of EAC and different CAF phenotypes found in the EAC patient TME. We evaluate cell phenotypes by combining tissue clearing techniques with wholemount immunofluorescence and histology, providing a practical framework for characterization of cancer assembloids.

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Section: Pdo-caf Assembloids Recapitulate Features Of Primary Tumorsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Patient-Derived Tumor Organoid and Fibroblast Assembloid Models for interrogation of the tumor microenvironment in Esophageal Adenocarcinoma

Sharpe,

Nazlamova,

Tse

et al. 2024

Preprint

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“…IL-6 signaling blockade has also been found to alter tumor immunosuppression by increasing tumor-infiltrating lymphocytes [ 89 ], and re-sensitizing esophageal cancer cells to chemoradiation therapy [ 90 ]. Strategies to directly prevent and reverse the activation of α-SMA-expressing myofibroblast CAFs in EAC have been proposed through phosphodiesterase type 5 inhibition [ 91 ], NAD(P)H Oxidase-4 blockade [ 92 ], and novel CAF-targeted near-infrared photoimmunotherapy [ 93 ]. Further studies are needed to define the mesenchymal compartment in EAC (and in esophageal cancer in general [ 94 ]), and, more importantly, to continue to explore the therapeutic potential of targeting CAFs.…”

Section: Fibroblasts In Esophageal Adenocarcinoma As a Target For Tre...mentioning

confidence: 99%

The role of the fibroblast in Barrett's esophagus and esophageal adenocarcinoma

Zhu,

Jin

2024

Current Opinion in Gastroenterology

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Purpose of review Barrett's esophagus (BE) is the number one risk factor for developing esophageal adenocarcinoma (EAC), a deadly cancer with limited treatment options that has been increasing in incidence in the US. In this report, we discuss current studies on the role of mesenchyme and cancer-associated fibroblasts (CAFs) in BE and EAC, and we highlight translational prospects of targeting these cells. Recent findings New insights through studies using single-cell RNA sequencing (sc-RNA seq) have revealed an important emerging role of the mesenchyme in developmental signaling and cancer initiation. BE and EAC share similar stromal gene expression, as functional classifications of nonepithelial cells in BE show a remarkable similarity to EAC CAFs. Several recent sc-RNA seq studies and novel organoid fibroblast co-culture systems have characterized the subgroups of fibroblasts in BE and EAC, and have shown that these cells can directly influence the epithelium to induce BE development and cancer progression. Targeting the CAFs in EAC with may be a promising novel therapeutic strategy. Summary The fibroblasts in the surrounding mesenchyme may have a direct role in influencing altered epithelial plasticity during BE development and progression to EAC.

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“…To understand whether the tumour micro-environment is linked to the prognostic groups, we calculated the TIDE (Tumor Immune Dysfunction and Exclusion) prediction score and quantified the T cell infiltration and exclusion within the tumour 47,52 . The TIDE score can be used to predict response to immunotherapy where a low TIDE score indicates potential for greater immunotherapy response.…”

Section: Rna Expression Analysismentioning

confidence: 99%

Radiomics biomarkers are associated with survival in patients with Oesophageal Adenocarcinoma

Aoude

Wong

Bonazzi

et al. 2023

Preprint

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Objective: Radiomics studies have shown promising results defining image surrogates that predict treatment response and survival in oesophageal squamous cell carcinoma. There are limited studies examining radiogenomics profiles in oesophageal adenocarcinoma (OAC) and this warrants further exploration. Background: Although advances have been made in the treatment of OAC, the five-year overall survival remains poor. Hence, there is a need for biomarkers to improve therapeutic approaches. Methods: Image analysis was performed on pre-treatment PET/CT scans from 80 OAC patients. In the discovery cohort (n=50), CT texture analysis was performed using a filtration-histogram method to evaluate the prognostic value of image features. Whole-genome sequencing, RNA sequencing (RNAseq) and immunohistochemistry characterised the molecular pathways associated with the CT markers. A validation cohort (n=30) was used to confirm radiomics biomarkers. Results: Analysis showed 3 CT markers were significantly associated with both disease-specific and disease-free survival. Combining these markers provided further prognostic significance. Furthermore, we identified a correlation between CT markers and major pathological response rate. Both RNAseq and immunohistochemistry confirmed that lower CD8 T-cell expression in the tumour correlated with the poor survival group predicted using CT markers. RNAseq gene set enrichment analysis identified pathways associated with these radiomics biomarkers. Finally, radiomics analysis in a validation cohort confirmed CT marker (SD, standard deviation) as a biomarker of survival and identified additional image features associated with patient survival. Conclusions: This study demonstrates that radiogenomics has the potential to identify OAC subgroups with prognostic significance and support clinical decision making.

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

Cited by 8 publications

References 75 publications

Patient-Derived Tumor Organoid and Fibroblast Assembloid Models for interrogation of the tumor microenvironment in Esophageal Adenocarcinoma

Patient-Derived Tumor Organoid and Fibroblast Assembloid Models for interrogation of the tumor microenvironment in Esophageal Adenocarcinoma

The role of the fibroblast in Barrett's esophagus and esophageal adenocarcinoma

Radiomics biomarkers are associated with survival in patients with Oesophageal Adenocarcinoma

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