Patient-derived explants, xenografts and organoids: 3-dimensional patient-relevant pre-clinical models in endometrial cancer

Collins, Anna; Miles, Gareth J; Wood, Joanna; MacFarlane, Marion; Pritchard, Catrin; Moss, Esther L.

doi:10.1016/j.ygyno.2019.11.020

Cited by 48 publications

(40 citation statements)

References 56 publications

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“…Pharmaceuticals 2021, 14, x FOR PEER REVIEW 3 of 16 higher rate of successful culture [17]. Both patient-derived organoid and xenograft models retain intratumoral heterogeneity, which is lacking in immortalized 2D cell lines [17]. A limitation of organoids as compared to xenografts is the absence of tumor vasculature.…”

Section: Tyrosine Kinase Receptor Signaling Pathways Are Downregulated By Cediranib But Not Bevacizumabmentioning

confidence: 99%

Advantages of Tyrosine Kinase Anti-Angiogenic Cediranib over Bevacizumab: Cell Cycle Abrogation and Synergy with Chemotherapy

Dixit

Zhang

et al. 2021

Pharmaceuticals

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Angiogenesis plays a crucial role in tumor development and metastasis. Both bevacizumab and cediranib have demonstrated activity as single anti-angiogenic agents in endometrial cancer, though subsequent studies of bevacizumab combined with chemotherapy failed to improve outcomes compared to chemotherapy alone. Our objective was to compare the efficacy of cediranib and bevacizumab in endometrial cancer models. The cellular effects of bevacizumab and cediranib were examined in endometrial cancer cell lines using extracellular signal-related kinase (ERK) phosphorylation, ligand shedding, cell viability, and cell cycle progression as readouts. Cellular viability was also tested in eight patient-derived organoid models of endometrial cancer. Finally, we performed a phosphoproteomic array of 875 phosphoproteins to define the signaling changes related to bevacizumab versus cediranib. Cediranib but not bevacizumab blocked ligand-mediated ERK activation in endometrial cancer cells. In both cell lines and patient-derived organoids, neither bevacizumab nor cediranib alone had a notable effect on cell viability. Cediranib but not bevacizumab promoted marked cell death when combined with chemotherapy. Cell cycle analysis demonstrated an accumulation in mitosis after treatment with cediranib + chemotherapy, consistent with the abrogation of the G2/M checkpoint and subsequent mitotic catastrophe. Molecular analysis of key controllers of the G2/M cell cycle checkpoint confirmed its abrogation. Phosphoproteomic analysis revealed that bevacizumab and cediranib had both similar and unique effects on cell signaling that underlie their shared versus individual actions as anti-angiogenic agents. An anti-angiogenic tyrosine kinase inhibitor such as cediranib has the potential to be superior to bevacizumab in combination with chemotherapy.

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Section: Tyrosine Kinase Receptor Signaling Pathways Are Downregulated By Cediranib But Not Bevacizumabmentioning

confidence: 99%

Advantages of Tyrosine Kinase Anti-Angiogenic Cediranib over Bevacizumab: Cell Cycle Abrogation and Synergy with Chemotherapy

Dixit

Zhang

et al. 2021

Pharmaceuticals

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“…In this study we have compared different approaches for evaluating changes in biomarker expression in response to anti-cancer drugs in PDEs. PDEs do not involve tumour deconstruction and therefore can be utilised to study drug responses in both tumour and stroma, and within different regions of the same tumour using spatial profiling ( 1 , 3 ). They therefore offer many advantages over other preclinical models for monitoring responses to agents that target the tumour microenvironment such as immunotherapies as well as for examining the role of tumour heterogeneity in influencing drug response.…”

Section: Discussionmentioning

confidence: 99%

Evaluating and comparing immunostaining and computational methods for spatial profiling of drug response in patient-derived explants

Miles

Powley

Mohammed

et al. 2021

Laboratory Investigation

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Patient Derived Explants (PDEs) represent the direct culture of fragments of freshly-resected tumour tissue under conditions that retain the original architecture of the tumour. PDEs have advantages over other preclinical cancer models as platforms for predicting patient-relevant drug responses in that they preserve the tumour microenvironment and tumour heterogeneity. At endpoint, PDEs may either be processed for generation of histological sections or homogenised and processed for “omic” evaluation of biomarker expression. A significant advantage of spatial profiling is the ability to co-register drug responses with tumour pathology, tumour heterogeneity and changes in the tumour microenvironment. Spatial profiling of PDEs relies on the utilisation of robust immunostaining approaches for validated biomarkers and incorporation of appropriate image analysis methods to quantitatively and qualitatively monitor changes in biomarker expression in response to anti-cancer drugs. Automation of immunostaining and image analysis would provide a significant advantage for the drug discovery pipeline and therefore, here, we have sought to optimise digital pathology approaches. We compare three image analysis software platforms (QuPath, ImmunoRatio and VisioPharm) for evaluating Ki67 as a marker for proliferation, cleaved PARP (cPARP) as a marker for apoptosis and pan-cytokeratin (CK) as a marker for tumour areas and find that all three generate comparable data to the views of a histomorphometrist. We also show that Virtual Double Staining of sequential sections by immunohistochemistry results in imperfect section alignment such that CK-stained tumour areas are over-estimated. Finally, we demonstrate that multi-immunofluorescence combined with digital image analysis is a superior method for monitoring multiple biomarkers simultaneously in tumour and stromal areas in PDEs.

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“…Air-liquid interfaces can be created by putting the OMS in contact with the culture media through a matrix (Geltrex, Matrigel, collagen) or membrane, by entrapping the OMS within gelatin or collagen, which is then put in the culture medium (“sponge method”). OMS can be used for drug testing ( 51 ) and biomarker discovery ( 52 ) as they represent valid patient pre-clinical models ( 53 , 54 ). Interestingly, PDEs can be implemented within a microfluidic platform ( 55 ) (please see the Organ-on-Chip section).…”

Section: D Modelsmentioning

confidence: 99%

“…This study is not the sole example of the use of OMS for Immunotherapy testing. OMS derived from pancreatic ductal carcinomas, endometrial cancer, and prostate cancer were used to study new approaches for checkpoint inhibitors and cytotoxic cell recruitment ( 54 , 57 , 58 ). Using models of colospheres generated from the HT29 and DLD-1 cell lines as well as a patient-derived CTO (colorectal tumor organoids) model, Liu et al evaluated the diffusion and distribution of Cetuximab, a monoclonal antibody targeting the extracellular model of the epidermal growth factor (EGFR) by MALDI-MSI.…”

Section: D Modelsmentioning

confidence: 99%

3D Tumor Models and Their Use for the Testing of Immunotherapies

Boucherit¹,

Gorvel²,

Olive³

2020

Front. Immunol.

118

100

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Over the past decade, immunotherapy has become a powerful and evident tool in the fight against cancers. Notably, the rise of checkpoint blockade using monoclonal antibodies (anti-CTLA4, anti-PD1) to avoid interaction between inhibitory molecules allowed the betterment of patient care. Indeed, immunotherapies led to increased overall survival in forms of cutaneous melanoma or lung cancer. However, the percentage of patients responding varies from 20 to 40% depending on the type of cancer and on the expression of the target molecules by the tumor. This is due to the tumor microenvironment which allows the acquisition of resistance mechanisms to immunotherapies by tumor cells. These are closely linked to the architecture and cellular composition of the tumor microenvironment. This one acts on different parameters such as the immune cells infiltrate its composition and therefore, favors the recruitment of immunosuppressive cells as well as the tumor expression of checkpoint inhibitors such as Programmed Death Ligand-1 (PD-L1). Therefore, the analysis and modeling of the complexity of the microenvironment is an important parameter to consider, not only in the search for new therapies but also for the identification and stratification of patients likely to respond to immunotherapy. This is why the use of 3D culture models, reflecting the architecture and cellular composition of a tumor, is essential in immuno-oncology studies. Nowadays, there are several 3-D culture methods such as spheroids and organoids, which are applicable to immuno-oncology. In this review we evaluate 3D culture models as tools for the development of treatments in the field of immuno-oncology.

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Patient-derived explants, xenografts and organoids: 3-dimensional patient-relevant pre-clinical models in endometrial cancer

Cited by 48 publications

References 56 publications

Advantages of Tyrosine Kinase Anti-Angiogenic Cediranib over Bevacizumab: Cell Cycle Abrogation and Synergy with Chemotherapy

Advantages of Tyrosine Kinase Anti-Angiogenic Cediranib over Bevacizumab: Cell Cycle Abrogation and Synergy with Chemotherapy

Evaluating and comparing immunostaining and computational methods for spatial profiling of drug response in patient-derived explants

3D Tumor Models and Their Use for the Testing of Immunotherapies

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