Establishment of patient-derived tumor spheroids for non-small cell lung cancer

Zhang, Zengli; Wang, Huiqian; Ding, Qifeng; Xing, Yufei; Xu, Zhonghua; Lu, Chia‐Wen; Luo, Dongdong; Xu, Longjiang; Xia, Wei; Zhou, Caicun; Shi, Minhua

doi:10.1371/journal.pone.0194016

Cited by 59 publications

(68 citation statements)

References 14 publications

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“…Future studies could involve drug screening on intricately designed vascularized systems for more physiological relevance in vitro outcomes 45 . Lastly, great strides have been made in the areas of microfluidics 46 and patient-derived spheroids 47 , so much so that one could envision future personalized clinical trials occurring in spheroids without the need for preclinical species 48 . In summary, the application of 3D cell culture and organs-on-a-chip for preclinical drug screening represents an exciting opportunity to accelerate the pace and success of drug discovery and development 49 .…”

Section: Discussionmentioning

confidence: 99%

Effects of microtubule-inhibiting small molecule and antibody-drug conjugate treatment on differentially-sized A431 squamous carcinoma spheroids

Durbin

Nottoli

Jenkins

2020

Sci Rep

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Multicellular tumor spheroids have been increasingly used by researchers to produce more physiologically relevant experimental environments. However, tracking of spheroid growth and treatment-induced volume reduction has not been readily adopted. Here, squamous carcinoma cells were seeded at different starting cell numbers with growth and reduction kinetics monitored using live cell imaging. Following the initial growth phase, spheroids were treated with auristatin as small molecule (MMAE) or as antibody-drug conjugate containing non-cleavable auristatin drug payload (033-F). Compared to cells in monolayers, 033-F had notably weaker potency against spheroids despite potency levels of MMAE being similar against monolayers and spheroids. Accumulation of released payload from 033-F was reduced in higher volume spheroids, likely contributing to the potency differences. Despite lowered potency towards spheroids with 033-F, spheroid volume was still readily reduced by 033-F in a dose-dependent fashion, with >85% volume reductions at the highest concentrations for all spheroid sizes. Additionally, the core of the larger spheroids showed more resiliency towards microtubule inhibition. Overall, this work highlights how various in-vivo 'features' such as tumor penetration, cell interactions, and increased resistance to therapeutics can be integrated into a spheroid model and tracked over time by automated imaging technology. In their native space, tumor cells experience interactions with neighboring cells over their entire surface area. This environment is vastly different than the conditions used for in vitro studies where cells attach to plastic dishes and grow in two-dimensions (2D) as monolayers. While many crucial molecular and cellular biology phenomena have been elucidated using cells cultivated on 2D surfaces, cell-to-cell communications, spatial orientation in the tissue, cell interactions with the surrounding matrix, and physiological signaling cannot be properly recreated 1. Growing cells into three-dimensional (3D) spheroids can better capture aspects of tumor biology such as regions of high oxygen, nutrients, and subsequently proliferation, as well as regions of low nutrients and hypoxia that can lead to cell quiescence and ultimately necrosis 2. A wide number of options for generating 3D spheroids has been put forth in the literature, including hanging drop, matrix-based methods, spinner flasks, and ultra-low adhesion plates, with each having its particular advantages and disadvantages 3. Due to approval rates under 10% for new therapeutics in oncology, improved methods of screening are needed to find better drugs to bring into clinical studies 4. More predictive models of drug efficacy and toxicity would help filter out candidates with a low chance of clinical success. Currently, many of the early-stage drug screens are performed with traditional 2D monolayers. Preclinical validation experiments typically lack many characteristics of the natural tumor milieu, instead presenting an environment that can be a s...

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Section: Discussionmentioning

confidence: 99%

Effects of microtubule-inhibiting small molecule and antibody-drug conjugate treatment on differentially-sized A431 squamous carcinoma spheroids

Durbin

Nottoli

Jenkins

2020

Sci Rep

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“…Tumor spheroids, one of the most versatile and common scaffold-free models [ 1 , 29 ], are typically obtained from single-cell suspensions that are self-assembling or forced to aggregate. These 3D microtissues are used to model a wide variety of tumors [ 60 – 63 ], reproducing, in particular, avascular tumor mass microregions [ 64 ], intervascular domains, and micrometastases [ 65 , 66 ]. Tumor spheroids of appropriate dimensions (> 500 μm in diameter) resemble the complex tumor scenario as they are composed of several specialized areas and layers where cells have different phenotypic, functional, and metabolic behaviors (Fig.…”

Section: Spheroid Modelmentioning

confidence: 99%

Modeling neoplastic disease with spheroids and organoids

et al. 2020

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Cancer is a complex disease in which both genetic defects and microenvironmental components contribute to the development, progression, and metastasization of disease, representing major hurdles in the identification of more effective and safer treatment regimens for patients. Three-dimensional (3D) models are changing the paradigm of preclinical cancer research as they more closely resemble the complex tissue environment and architecture found in clinical tumors than in bidimensional (2D) cell cultures. Among 3D models, spheroids and organoids represent the most versatile and promising models in that they are capable of recapitulating the heterogeneity and pathophysiology of human cancers and of filling the gap between conventional 2D in vitro testing and animal models. Such 3D systems represent a powerful tool for studying cancer biology, enabling us to model the dynamic evolution of neoplastic disease from the early stages to metastatic dissemination and the interactions with the microenvironment. Spheroids and organoids have recently been used in the field of drug discovery and personalized medicine. The combined use of 3D models could potentially improve the robustness and reliability of preclinical research data, reducing the need for animal testing and favoring their transition to clinical practice. In this review, we summarize the recent advances in the use of these 3D systems for cancer modeling, focusing on their innovative translational applications, looking at future challenges, and comparing them with most widely used animal models.

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“…To address these issues, 3D cell culture models are a reliable alternative, providing experimentally accessible human models to study the biological processes of cancer. Several 3D culture platforms such as spheroids, organoids, hydrogels, 3D scaffolds, 3D bio-printing, and microfluidics have attempted the recreation of certain aspects of tumor microenvironments present in tissues including the brain [30][31][32][33][34][35][36], breast [37][38][39][40][41][42][43], ovarian [44][45][46][47][48][49][50][51], bone [52][53][54][55][56][57][58], liver [59][60][61][62][63][64][65], lung [66][67][68][69][70][71][72], colon [73][74][75][76]…”

Section: Mimicking Tme In Three-dimensionsmentioning

confidence: 99%

Mimicking tumor hypoxia and tumor-immune interactions employing three-dimensional in vitro models

Bhattacharya

Calar

Puente

2020

J Exp Clin Cancer Res

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The heterogeneous tumor microenvironment (TME) is highly complex and not entirely understood. These complex configurations lead to the generation of oxygen-deprived conditions within the tumor niche, which modulate several intrinsic TME elements to promote immunosuppressive outcomes. Decoding these communications is necessary for designing effective therapeutic strategies that can effectively reduce tumor-associated chemotherapy resistance by employing the inherent potential of the immune system. While classic two-dimensional in vitro research models reveal critical hypoxia-driven biochemical cues, threedimensional (3D) cell culture models more accurately replicate the TME-immune manifestations. In this study, we review various 3D cell culture models currently being utilized to foster an oxygen-deprived TME, those that assess the dynamics associated with TME-immune cell penetrability within the tumor-like spatial structure, and discuss state of the art 3D systems that attempt recreating hypoxia-driven TME-immune outcomes. We also highlight the importance of integrating various hallmarks, which collectively might influence the functionality of these 3D models. This review strives to supplement perspectives to the quickly-evolving discipline that endeavors to mimic tumor hypoxia and tumor-immune interactions using 3D in vitro models.

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Establishment of patient-derived tumor spheroids for non-small cell lung cancer

Cited by 59 publications

References 14 publications

Effects of microtubule-inhibiting small molecule and antibody-drug conjugate treatment on differentially-sized A431 squamous carcinoma spheroids

Effects of microtubule-inhibiting small molecule and antibody-drug conjugate treatment on differentially-sized A431 squamous carcinoma spheroids

Modeling neoplastic disease with spheroids and organoids

Mimicking tumor hypoxia and tumor-immune interactions employing three-dimensional in vitro models

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