Micro-dissected tumor tissues on chip: an ex vivo method for drug testing and personalized therapy

Lab on a Chip ◽  
2016 ◽  
Vol 16 (2) ◽  
pp. 312-325 ◽  
Author(s):  
M. Astolfi ◽  
B. Péant ◽  
M. A. Lateef ◽  
N. Rousset ◽  
J. Kendall-Dupont ◽  
...  

Micro-dissected tumor tissues (MDTs) are maintained alive on chip for several days and show promising results for personalized medicine applications.

2021 ◽  
Vol 22 (7) ◽  
pp. 3483
Author(s):  
Colin Rae ◽  
Francesco Amato ◽  
Chiara Braconi

In the search for the ideal model of tumours, the use of three-dimensional in vitro models is advancing rapidly. These are intended to mimic the in vivo properties of the tumours which affect cancer development, progression and drug sensitivity, and take into account cell–cell interactions, adhesion and invasiveness. Importantly, it is hoped that successful recapitulation of the structure and function of the tissue will predict patient response, permitting the development of personalized therapy in a timely manner applicable to the clinic. Furthermore, the use of co-culture systems will allow the role of the tumour microenvironment and tissue–tissue interactions to be taken into account and should lead to more accurate predictions of tumour development and responses to drugs. In this review, the relative merits and limitations of patient-derived organoids will be discussed compared to other in vitro and ex vivo cancer models. We will focus on their use as models for drug testing and personalized therapy and how these may be improved. Developments in technology will also be considered, including the use of microfluidics, 3D bioprinting, cryopreservation and circulating tumour cell-derived organoids. These have the potential to enhance the consistency, accessibility and availability of these models.


2020 ◽  
Vol 138 ◽  
pp. S59
Author(s):  
N. Beztsinna ◽  
F. Grillet ◽  
A. Jariani ◽  
J. Overkamp ◽  
D. van der Meer ◽  
...  

2021 ◽  
Author(s):  
Nataliia Beztsinna ◽  
Fanny Grillet ◽  
Niels Meesters ◽  
Donny van der Meer ◽  
Lidia Daszkiewicz ◽  
...  

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3727
Author(s):  
Dafne Jacome Sanz ◽  
Juuli Raivola ◽  
Hanna Karvonen ◽  
Mariliina Arjama ◽  
Harlan Barker ◽  
...  

Background: Dysregulated lipid metabolism is emerging as a hallmark in several malignancies, including ovarian cancer (OC). Specifically, metastatic OC is highly dependent on lipid-rich omentum. We aimed to investigate the therapeutic value of targeting lipid metabolism in OC. For this purpose, we studied the role of PCSK9, a cholesterol-regulating enzyme, in OC cell survival and its downstream signaling. We also investigated the cytotoxic efficacy of a small library of metabolic (n = 11) and mTOR (n = 10) inhibitors using OC cell lines (n = 8) and ex vivo patient-derived cell cultures (PDCs, n = 5) to identify clinically suitable drug vulnerabilities. Targeting PCSK9 expression with siRNA or PCSK9 specific inhibitor (PF-06446846) impaired OC cell survival. In addition, overexpression of PCSK9 induced robust AKT phosphorylation along with increased expression of ERK1/2 and MEK1/2, suggesting a pro-survival role of PCSK9 in OC cells. Moreover, our drug testing revealed marked differences in cytotoxic responses to drugs targeting metabolic pathways of high-grade serous ovarian cancer (HGSOC) and low-grade serous ovarian cancer (LGSOC) PDCs. Our results show that targeting PCSK9 expression could impair OC cell survival, which warrants further investigation to address the dependency of this cancer on lipogenesis and omental metastasis. Moreover, the differences in metabolic gene expression and drug responses of OC PDCs indicate the existence of a metabolic heterogeneity within OC subtypes, which should be further explored for therapeutic improvements.


2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi221-vi222
Author(s):  
Gerhard Jungwirth ◽  
Tao Yu ◽  
Cao Junguo ◽  
Catharina Lotsch ◽  
Andreas Unterberg ◽  
...  

Abstract Tumor-organoids (TOs) are novel, complex three-dimensional ex vivo tissue cultures that under optimal conditions accurately reflect genotype and phenotype of the original tissue with preserved cellular heterogeneity and morphology. They may serve as a new and exciting model for studying cancer biology and directing personalized therapies. The aim of our study was to establish TOs from meningioma (MGM) and to test their usability for large-scale drug screenings. We were capable of forming several hundred TO equal in size by controlled reaggregation of freshly prepared single cell suspension of MGM tissue samples. In total, standardized TOs from 60 patients were formed, including eight grade II and three grade III MGMs. TOs reaggregated within 3 days resulting in a reducted diameter by 50%. Thereafter, TO size remained stable throughout a 14 days observation period. TOs consisted of largely viable cells, whereas dead cells were predominantly found outside of the organoid. H&E stainings confirmed the successful establishment of dense tissue-like structures. Next, we assessed the suitability and reliability of TOs for a robust large-scale drug testing by employing nine highly potent compounds, derived from a drug screening performed on several MGM cell lines. First, we tested if drug responses depend on TO size. Interestingly, drug responses to these drugs remained identical independent of their sizes. Based on a sufficient representation of low abundance cell types such as T-cells and macrophages an overall number of 25.000 cells/TO was selected for further experiments revealing FDA-approved HDAC inhibitors as highly effective drugs in most of the TOs with a mean z-AUC score of -1.33. Taken together, we developed a protocol to generate standardized TO from MGM containing low abundant cell types of the tumor microenvironment in a representative manner. Robust and reliable drug responses suggest patient-derived TOs as a novel drug testing model in meningioma research.


2020 ◽  
Vol 122 (6) ◽  
pp. 735-744 ◽  
Author(s):  
Ian R. Powley ◽  
Meeta Patel ◽  
Gareth Miles ◽  
Howard Pringle ◽  
Lynne Howells ◽  
...  

AbstractPreclinical models that can accurately predict outcomes in the clinic are much sought after in the field of cancer drug discovery and development. Existing models such as organoids and patient-derived xenografts have many advantages, but they suffer from the drawback of not contextually preserving human tumour architecture. This is a particular problem for the preclinical testing of immunotherapies, as these agents require an intact tumour human-specific microenvironment for them to be effective. In this review, we explore the potential of patient-derived explants (PDEs) for fulfilling this need. PDEs involve the ex vivo culture of fragments of freshly resected human tumours that retain the histological features of original tumours. PDE methodology for anti-cancer drug testing has been in existence for many years, but the platform has not been widely adopted in translational research facilities, despite strong evidence for its clinical predictivity. By modifying PDE endpoint analysis to include the spatial profiling of key biomarkers by using multispectral imaging, we argue that PDEs offer many advantages, including the ability to correlate drug responses with tumour pathology, tumour heterogeneity and changes in the tumour microenvironment. As such, PDEs are a powerful model of choice for cancer drug and biomarker discovery programmes.


RSC Advances ◽  
2018 ◽  
Vol 8 (65) ◽  
pp. 36987-36998 ◽  
Author(s):  
Shengli Mi ◽  
Baihan Li ◽  
Xiaoman Yi ◽  
Yuanyuan Xu ◽  
Zhichang Du ◽  
...  

Liver-on-chip, due to its precision and low cost for constructing in vitro models, has tremendous potential for drug toxicity testing and pathological studies.


2020 ◽  
Vol 26 (3) ◽  
pp. 179-192 ◽  
Author(s):  
Swati Sharma ◽  
Bastien Venzac ◽  
Thomas Burgers ◽  
Séverine Le Gac ◽  
Stefan Schlatt

Abstract The significant rise in male infertility disorders over the years has led to extensive research efforts to recapitulate the process of male gametogenesis in vitro and to identify essential mechanisms involved in spermatogenesis, notably for clinical applications. A promising technology to bridge this research gap is organ-on-chip (OoC) technology, which has gradually transformed the research landscape in ART and offers new opportunities to develop advanced in vitro culture systems. With exquisite control on a cell or tissue microenvironment, customized organ-specific structures can be fabricated in in vitro OoC platforms, which can also simulate the effect of in vivo vascularization. Dynamic cultures using microfluidic devices enable us to create stimulatory effect and non-stimulatory culture conditions. Noteworthy is that recent studies demonstrated the potential of continuous perfusion in OoC systems using ex vivo mouse testis tissues. Here we review the existing literature and potential applications of such OoC systems for male reproduction in combination with novel bio-engineering and analytical tools. We first introduce OoC technology and highlight the opportunities offered in reproductive biology in general. In the subsequent section, we discuss the complex structural and functional organization of the testis and the role of the vasculature-associated testicular niche and fluid dynamics in modulating testis function. Next, we review significant technological breakthroughs in achieving in vitro spermatogenesis in various species and discuss the evidence from microfluidics-based testes culture studies in mouse. Lastly, we discuss a roadmap for the potential applications of the proposed testis-on-chip culture system in the field of primate male infertility, ART and reproductive toxicology.


Lab on a Chip ◽  
2020 ◽  
Vol 20 (12) ◽  
pp. 2228-2236 ◽  
Author(s):  
Xuejia Hu ◽  
Shukun Zhao ◽  
Ziyi Luo ◽  
Yunfeng Zuo ◽  
Fang Wang ◽  
...  

Multicellular aggregates in three-dimensional (3D) environments provide novel solid tumor models that can provide insight into in vivo drug resistance.


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