Challenges and Opportunities Toward Enabling Phenotypic Screening of Complex and 3D Cell Models

Horman, Shane R.; Hogan, Christopher; Reyes, Karlo Delos; Lo, Frederick; Antczak, Christophe

doi:10.4155/fmc.14.163

Cited by 19 publications

(22 citation statements)

References 63 publications

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“…Even though NCPs do not overcome all of the above mentioned disadvantages (e.g., lack of vasculature, expensive) inherent to working with 3D cell cultures, they overcome flaws of other scaffold‐type 3D culture systems such as lot‐to‐lot variation, difficulty of imaging, and cumbersome culturing workflows (Yoshii et al, ). Growing spheroids using NCPs is also suitable for high‐throughput screening and offers great potential for future integration into contemporary drug screening procedures (Horman, Hogan, Delos Reyes, Lo, & Antczak, ).…”

Section: Scaffold and Non‐scaffold Techniquesmentioning

confidence: 99%

Three‐dimensional cell culture models for anticancer drug screening: Worth the effort?

Verjans

Doijen

Luyten

et al. 2017

Journal Cellular Physiology

168

185

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High attrition of new oncology drug candidates in clinical trials is partially caused by the poor predictive capacity of artificial monolayer cell culture assays early in drug discovery. Monolayer assays do not take the natural three-dimensional (3D) microenvironment of cells into account. As a result, false positive compounds often enter clinical trials, leading to high dropout rates and a waste of time and money. Over the past 2 decades, tissue engineers and cell biologists have developed a broad range of 3D in vitro culturing tools that better represent in vivo cell biology. These tools preserve the 3D architecture of cells and can be used to predict toxicity of and resistance against antitumor agents. Recent progress in tissue engineering further improves 3D models by taking into account the tumor microenvironment, which is important for metastatic progression and vascularization. However, the widespread implementation of 3D cell cultures into cell-based research programs has been limited by various factors, including their cost and reproducibility. In addition, different 3D cell culture techniques often produce spheroids of different size and shape, which can strongly influence drug efficacy and toxicity. Hence, it is imperative to morphometrically characterize multicellular spheroids to avoid generalizations among different spheroid types. Standardized 3D culturing procedures could further reduce data variability and enhance biological relevance. Here, we critically evaluate the benefits and challenges inherent to growing cells in 3D, along with an overview of the techniques used to form spheroids. This is done with a specific focus on antitumor drug screening.

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Section: Scaffold and Non‐scaffold Techniquesmentioning

confidence: 99%

Three‐dimensional cell culture models for anticancer drug screening: Worth the effort?

Verjans

Doijen

Luyten

et al. 2017

Journal Cellular Physiology

168

185

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“…These co-culture systems combining stromal and tumoral cells seem to be the best methods to model heterotypic cell-cell interactions. However, the implementation of standardized co-cultures that include different cell types remains challenging, and reducing the tumor ecosystem to a few of the main components that are expected to be involved in the tumor biology may be enough to establish models with superior predictive power over the conventional 2D mono-cultures of tumor cells [18, 19]. …”

Section: Introductionmentioning

confidence: 99%

Identification of an easy to use 3D culture model to investigate invasion and anticancer drug response in chondrosarcomas

et al. 2017

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BackgroundCytotoxic efficacy of anticancer drugs has been widely studied with monolayer-cultured cancer cells. However, the efficacy of drugs under two-dimensional (2D) culture condition usually differs from that of three-dimensional (3D) one. In the present study, an in vitro tumor tissue model was constructed using alginate hydrogel, and in vitro cytotoxic efficacy of two anticancer drugs (cisplatin and DZNep) was investigated in chondrosarcomas, and compared to in vivo response.MethodsThree cell lines derived from human chondrosarcomas, CH2879, JJ012 and SW1353, were embedded in alginate hydrogel. Proliferation and survival were assayed by ATP measurement using Cell Titer-Glo luminescent cell viability assay kit, and by counting viable cells in beads. Collagen and COMP expression was determined by RT-PCR. Invasion/migration was estimated by counting cells leaving alginate beads and adhering to culture dish. Then, chondrosarcoma response to cisplatin and DZNep was compared between cells cultured in monolayer or embedded in alginate, and using chondrosarcoma xenografts in nude mice.ResultsChondrosarcomas survived at least for 8 weeks, after embedment in alginate. However, only CH2879 cells could proliferate. Also, this cell line is more invasive than SW1353 and JJ012, which was coherent with the grade of their respective primary tumors. Furthermore, the expression of type II collagen was higher in chondrosarcomas cultured in 3D than in 2D. Interestingly, this 3D culture system allows to validate the absence of response of chondrosarcomas to cisplatin, and to predict the efficiency of DZNep to reduce chondrosarcoma growth in vivo.ConclusionsThis study validates alginate beads as a relevant 3D model to study cancer biology and tumor responses to biological treatments.

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“…However, small-molecule screening with more complex 3D cell assemblies has not yet reached its full potential, as it adds another layer of complexity on top of the challenges of hiPSCbased screening (Arlotta, 2018;Horman et al, 2015;Moffat et al, 2014). Industrial implementation requires extreme reproducibility and efficient, automated workflows to leverage the economy of scale.…”

Section: Challenges Of Stem Cell-based Pts In 2d Culturesmentioning

confidence: 99%

The Convergence of Stem Cell Technologies and Phenotypic Drug Discovery

Friese

Ursu

Hochheimer³

et al. 2019

Cell Chemical Biology

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Recent advances in induced pluripotent stem cell technologies and phenotypic screening shape the future of bioactive small-molecule discovery. In this review we analyze the impact of small-molecule phenotypic screens on drug discovery as well as on the investigation of human development and disease biology. We further examine the role of 3D spheroid/organoid structures, microfluidic systems, and miniaturized on-achip systems for future discovery strategies. In highlighting representative examples, we analyze how recent achievements can translate into future therapies. Finally, we discuss remaining challenges that need to be overcome for the adaptation of the next generation of screening approaches.

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Challenges and Opportunities Toward Enabling Phenotypic Screening of Complex and 3D Cell Models

Cited by 19 publications

References 63 publications

Three‐dimensional cell culture models for anticancer drug screening: Worth the effort?

Three‐dimensional cell culture models for anticancer drug screening: Worth the effort?

Identification of an easy to use 3D culture model to investigate invasion and anticancer drug response in chondrosarcomas

The Convergence of Stem Cell Technologies and Phenotypic Drug Discovery

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