Special Issue "Patient-Derived Xenograft-Models in Cancer Research"

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 March 2020).

Special Issue Editor

Dr. Wytske van Weerden
Website
Guest Editor
Department of Urology, Erasmus University, Rotterdam, The Netherlands.
Interests: patient-derived models: xenografts, ex vivo tissue slices and organoid cultures; therapy resistance: castration-resistance, taxane-resistance, radioresistance; targeted imaging and radionuclide therapy: anti-PSMA and bombesin analogs; immune therapy of prostate cancer; metastasis

Special Issue Information

Dear Colleagues,

Conventional (2D) cell culture models are great for relatively fast and easy research, but they do not reflect the heterogeneity of clinical cancer. Realizing that models are needed that more faithfully reflect tumor complexity, a revaluation of patient-derived xenograft (PDX) models has taken place in the last two decades, instigating a revival of their use in fundamental and translational cancer research.

With the recognition that xenograft models are essential for investigating crucial aspects of tumor biology, such as tumor microenvironment, including vascularity, metastasis, and immune responses, we are, at the same time, confronted with the societal request to reduce animal research. Increasing efforts for more humanized models and with improving technology, we are now able to use optimized PDX models and highly dedicated multimodality imaging to reduce animal numbers needed for our research. Alternative PDX-based culture systems are being developed and optimized to fuel into in vitro primary (organoid) cultures and ex vivo precision-cut tissue slices.

With this Special Issue of Cancers, we wish to share cutting-edge developments and exchange expertise and know-how that are relevant across cancer types. We welcome authors to submit original research articles that will address research topics that require PDX models, highlighting their translational power:

  • Tumor microenvironment
  • Metastasis
  • Tumor immunology
  • Alternative PDX modeling: 3D organoids and tissue slice

Dr. Wytske van Weerden
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2000 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • patient-derived xenograft models
  • tumor biology
  • tumor microenvironment
  • metastasis
  • tumor immunology
  • thin-cut tissue slices
  • organoids

Published Papers (8 papers)

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Research

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Open AccessArticle
Impact of the Injection Site on Growth Characteristics, Phenotype and Sensitivity towards Cytarabine of Twenty Acute Leukaemia Patient-Derived Xenograft Models
Cancers 2020, 12(5), 1349; https://doi.org/10.3390/cancers12051349 - 25 May 2020
Abstract
Rodent models have contributed significantly to the understanding of haematological malignancies. One important model system in this context are patient-derived xenografts (PDX). In the current study, we examined 20 acute leukaemia PDX models for growth behaviour, infiltration in haemopoietic organs and sensitivity towards [...] Read more.
Rodent models have contributed significantly to the understanding of haematological malignancies. One important model system in this context are patient-derived xenografts (PDX). In the current study, we examined 20 acute leukaemia PDX models for growth behaviour, infiltration in haemopoietic organs and sensitivity towards cytarabine. PDX were injected intratibially (i.t.), intrasplenicaly (i.s.) or subcutaneously (s.c.) into immune compromised mice. For 18/20 models the engraftment capacity was independent of the implantation site. Two models could exclusively be propagated in one or two specific settings. The implantation site did influence tumour growth kinetics as median overall survival differed within one model depending on the injection route. The infiltration pattern was similar in i.t. and i.s. models. In contrast to the s.c. implantation, only one model displayed circulating leukaemic cells outside of the locally growing tumour mass. Cytarabine was active in all four tested models. Nevertheless, the degree of sensitivity was specific for an individual model and implantation site. In summary, all three application routes turned out to be feasible for the propagation of PDX. Nevertheless, the distinct differences between the settings highlight the need for well characterized platforms to ensure the meaningful interpretation of data generated using those powerful tools. Full article
(This article belongs to the Special Issue Patient-Derived Xenograft-Models in Cancer Research)
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Open AccessArticle
Multi-Modal PET and MR Imaging in the Hen’s Egg Test-Chorioallantoic Membrane (HET-CAM) Model for Initial In Vivo Testing of Target-Specific Radioligands
Cancers 2020, 12(5), 1248; https://doi.org/10.3390/cancers12051248 - 15 May 2020
Abstract
The validation of novel target-specific radioligands requires animal experiments mostly using mice with xenografts. A pre-selection based on a simpler in vivo model would allow to reduce the number of animal experiments, in accordance with the 3Rs principles (reduction, replacement, refinement). In this [...] Read more.
The validation of novel target-specific radioligands requires animal experiments mostly using mice with xenografts. A pre-selection based on a simpler in vivo model would allow to reduce the number of animal experiments, in accordance with the 3Rs principles (reduction, replacement, refinement). In this respect, the chick embryo or hen’s egg test–chorioallantoic membrane (HET-CAM) model is of special interest, as it is not considered an animal until day 17. Thus, we evaluated the feasibility of quantitative analysis of target-specific radiotracer accumulation in xenografts using the HET-CAM model and combined positron emission tomography (PET) and magnetic resonance imaging (MRI). For proof-of-principle we used established prostate-specific membrane antigen (PSMA)-positive and PSMA-negative prostate cancer xenografts and the clinically widely used PSMA-specific PET-tracer [68Ga]Ga-PSMA-11. Tracer accumulation was quantified by PET and tumor volumes measured with MRI (n = 42). Moreover, gamma-counter analysis of radiotracer accumulation was done ex-vivo. A three- to five-fold higher ligand accumulation in the PSMA-positive tumors compared to the PSMA-negative tumors was demonstrated. This proof-of-principle study shows the general feasibility of the HET-CAM xenograft model for target-specific imaging with PET and MRI. The ultimate value for characterization of novel target-specific radioligands now has to be validated in comparison to mouse xenograft experiments. Full article
(This article belongs to the Special Issue Patient-Derived Xenograft-Models in Cancer Research)
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Open AccessArticle
Establishment and Characterization of Humanized Mouse NPC-PDX Model for Testing Immunotherapy
Cancers 2020, 12(4), 1025; https://doi.org/10.3390/cancers12041025 - 22 Apr 2020
Abstract
Immune checkpoint blockade (ICB) monotherapy shows early promise for the treatment of nasopharyngeal carcinoma (NPC) in patients. Nevertheless, limited representative NPC models hamper preclinical studies to evaluate the efficacy of novel ICB and combination regimens. In the present study, we engrafted NPC biopsies [...] Read more.
Immune checkpoint blockade (ICB) monotherapy shows early promise for the treatment of nasopharyngeal carcinoma (NPC) in patients. Nevertheless, limited representative NPC models hamper preclinical studies to evaluate the efficacy of novel ICB and combination regimens. In the present study, we engrafted NPC biopsies in non-obese diabetic-severe combined immunodeficiency interleukin-2 receptor gamma chain-null (NSG) mice and established humanized mouse NPC-patient-derived xenograft (NPC-PDX) model successfully. Epstein–Barr virus was detected in the NPC in both NSG and humanized mice as revealed by Epstein–Barr virus-encoded small RNA (EBER) in situ hybridization (ISH) and immunohistochemical (IHC) staining. In the NPC-bearing humanized mice, the percentage of tumor-infiltrating CD8+ cytotoxic T cells was lowered, and the T cells expressed higher levels of various inhibitory receptors, such as programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) than those in blood. The mice were then treated with nivolumab and ipilimumab, and the anti-tumor efficacy of combination immunotherapy was examined. In line with paired clinical data, the NPC-PDX did not respond to the treatment in terms of tumor burden, whilst an immunomodulatory response was elicited in the humanized mice. From our results, human proinflammatory cytokines, such as interferon-gamma (IFN-γ) and interleukin-6 (IL-6) were significantly upregulated in plasma. After treatment, there was a decrease in CD4/CD8 ratio in the NPC-PDX, which also simulated the modulation of intratumoral CD4/CD8 profile from the corresponding donor. In addition, tumor-infiltrating T cells were re-activated and secreted more IFN-γ towards ex vivo stimulation, suggesting that other factors, including soluble mediators and metabolic milieu in tumor microenvironment may counteract the effect of ICB treatment and contribute to the tumor progression in the mice. Taken together, we have established and characterized a novel humanized mouse NPC-PDX model, which plausibly serves as a robust platform to test for the efficacy of immunotherapy and may predict clinical outcomes in NPC patients. Full article
(This article belongs to the Special Issue Patient-Derived Xenograft-Models in Cancer Research)
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Open AccessFeature PaperArticle
Establishment and Characterisation of Heterotopic Patient-Derived Xenografts for Glioblastoma
Cancers 2020, 12(4), 871; https://doi.org/10.3390/cancers12040871 - 03 Apr 2020
Abstract
Glioblastoma is an aggressive brain tumour with a patient median survival of approximately 14 months. The development of innovative treatment strategies to increase the life span and quality of life of patients is hence essential. This requires the use of appropriate glioblastoma models [...] Read more.
Glioblastoma is an aggressive brain tumour with a patient median survival of approximately 14 months. The development of innovative treatment strategies to increase the life span and quality of life of patients is hence essential. This requires the use of appropriate glioblastoma models for preclinical testing, which faithfully reflect human cancers. The aim of this study was to establish glioblastoma patient-derived xenografts (PDXs) by heterotopic transplantation of tumour pieces in the axillae of NMRI nude mice. Ten out of 22 patients’ samples gave rise to tumours in mice. Their human origin was confirmed by microsatellite analyses, though minor changes were observed. The glioblastoma nature of the PDXs was corroborated by pathological evaluation. Latency times spanned from 48.5 to 370.5 days in the first generation. Growth curve analyses revealed an increase in the growth rate with increasing passages. The methylation status of the MGMT promoter in the primary material was maintained in the PDXs. However, a trend towards a more methylated pattern could be found. A correlation was observed between the take in mice and the proportion of Sox2+ cells (r = 0.49, p = 0.016) and nestin+ cells (r = 0.55, p = 0.007). Our results show that many PDXs maintain key features of the patients’ samples they derive from. They could thus be used as preclinical models to test new therapies and biomarkers. Full article
(This article belongs to the Special Issue Patient-Derived Xenograft-Models in Cancer Research)
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Open AccessArticle
A Model of a Zebrafish Avatar for Co-Clinical Trials
Cancers 2020, 12(3), 677; https://doi.org/10.3390/cancers12030677 - 13 Mar 2020
Cited by 1
Abstract
Animal “avatars” and co-clinical trials are being developed for possible use in personalized medicine in oncology. In a co-clinical trial, the cancer cells of the patient’s tumor are xenotransplanted into the animal avatar for drug efficacy studies, and the data collected in the [...] Read more.
Animal “avatars” and co-clinical trials are being developed for possible use in personalized medicine in oncology. In a co-clinical trial, the cancer cells of the patient’s tumor are xenotransplanted into the animal avatar for drug efficacy studies, and the data collected in the animal trial are used to plan the best drug treatment in the patient trial. Zebrafish have recently been proposed for implementing avatar models, however the lack of a general criterion for the chemotherapy dose conversion from humans to fish is a limitation in terms of conducting co-clinical trials. Here, we validate a simple, reliant and cost-effective avatar model based on the use of zebrafish embryos. By crossing data from safety and efficacy studies, we found a basic formula for estimating the equivalent dose for use in co-clinical trials which we validated in a clinical study enrolling 24 adult patients with solid cancers (XenoZ, NCT03668418). Full article
(This article belongs to the Special Issue Patient-Derived Xenograft-Models in Cancer Research)
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Open AccessArticle
Novel Breast Cancer Brain Metastasis Patient-Derived Orthotopic Xenograft Model for Preclinical Studies
Cancers 2020, 12(2), 444; https://doi.org/10.3390/cancers12020444 - 14 Feb 2020
Abstract
The vast majority of mortality in breast cancer results from distant metastasis. Brain metastases occur in as many as 30% of patients with advanced breast cancer, and the 1-year survival rate of these patients is around 20%. Pre-clinical animal models that reliably reflect [...] Read more.
The vast majority of mortality in breast cancer results from distant metastasis. Brain metastases occur in as many as 30% of patients with advanced breast cancer, and the 1-year survival rate of these patients is around 20%. Pre-clinical animal models that reliably reflect the biology of breast cancer brain metastasis are needed to develop and test new treatments for this deadly condition. The patient-derived xenograft (PDX) model maintains many features of a donor tumor, such as intra-tumor heterogeneity, and permits the testing of individualized treatments. However, the establishment of orthotopic PDXs of brain metastasis is procedurally difficult. We have developed a method for generating such PDXs with high tumor engraftment and growth rates. Here, we describe this method and identify variables that affect its outcomes. We also compare the brain-orthotopic PDXs with ectopic PDXs grown in mammary pads of mice, and show that the responsiveness of PDXs to chemotherapeutic reagents can be dramatically affected by the site that they are in. Full article
(This article belongs to the Special Issue Patient-Derived Xenograft-Models in Cancer Research)
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Review

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Open AccessReview
Patient-Derived Xenograft Models of Pancreatic Cancer: Overview and Comparison with Other Types of Models
Cancers 2020, 12(5), 1327; https://doi.org/10.3390/cancers12051327 - 22 May 2020
Abstract
Pancreatic cancer (PC) is anticipated to be second only to lung cancer as the leading cause of cancer-related deaths in the United States by 2030. Surgery remains the only potentially curative treatment for patients with pancreatic ductal adenocarcinoma (PDAC), the most common form [...] Read more.
Pancreatic cancer (PC) is anticipated to be second only to lung cancer as the leading cause of cancer-related deaths in the United States by 2030. Surgery remains the only potentially curative treatment for patients with pancreatic ductal adenocarcinoma (PDAC), the most common form of PC. Multiple recent preclinical studies focus on identifying effective treatments for PDAC, but the models available for these studies often fail to reproduce the heterogeneity of this tumor type. Data generated with such models are of unknown clinical relevance. Patient-derived xenograft (PDX) models offer several advantages over human cell line-based in vitro and in vivo models and models of non-human origin. PDX models retain genetic characteristics of the human tumor specimens from which they were derived, have intact stromal components, and are more predictive of patient response than traditional models. This review briefly describes the advantages and disadvantages of 2D cultures, organoids and genetically engineered mouse (GEM) models of PDAC, and focuses on the applications, characteristics, advantages, limitations, and the future potential of PDX models for improving the management of PDAC. Full article
(This article belongs to the Special Issue Patient-Derived Xenograft-Models in Cancer Research)
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Open AccessReview
Patient-Derived Xenograft Models in Urological Malignancies: Urothelial Cell Carcinoma and Renal Cell Carcinoma
Cancers 2020, 12(2), 439; https://doi.org/10.3390/cancers12020439 - 13 Feb 2020
Cited by 1
Abstract
The engraftment of human tumor tissues into immunodeficient host mice to generate patient-derived xenograft (PDX) models has become increasingly utilized for many types of cancers. By capturing the unique genomic and molecular properties of the parental tumor, PDX models enable analysis of patient-specific [...] Read more.
The engraftment of human tumor tissues into immunodeficient host mice to generate patient-derived xenograft (PDX) models has become increasingly utilized for many types of cancers. By capturing the unique genomic and molecular properties of the parental tumor, PDX models enable analysis of patient-specific clinical responses. PDX models are an important platform to address the contribution of inter-tumoral heterogeneity to therapeutic sensitivity, tumor evolution, and the mechanisms of treatment resistance. With the increasingly important role played by targeted therapies in urological malignancies, the establishment of representative PDX models can contribute to improved facilitation and adoption of precision medicine. In this review of the evolving role of the PDX in urothelial cancer and kidney cancer, we discuss the essential elements of successful graft development, effective translational application, and future directions for clinical models. Full article
(This article belongs to the Special Issue Patient-Derived Xenograft-Models in Cancer Research)
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