A Microfluidic Cancer-on-Chip Platform Predicts Drug Response Using Organotypic Tumor Slice Culture

Chakrabarty, Sanjiban; Quiros-Solano, William F.; Kuijten, Maayke MP; Haspels, Ben; Mallya, Sandeep; Lo, Calvin Shun Yu; Othman, Amr A.; Silvestri, Cinzia; Stolpe, Anja van de; Gaio, Nikolas; Odijk, Hanny; Ven, Marieke van de; Ridder, Corrina M.A. de; Weerden, Wytske M. van; Jonkers, Jos; Dekker, R.; Taneja, Nitika; Kanaar, Roland; Gent, Dik C. van

doi:10.1158/0008-5472.can-21-0799

Cited by 29 publications

(37 citation statements)

References 54 publications

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“…The relevance of the method is now supported by PDX experiments. Chakrabarty et al [ 22 ] have shown that tumor-derived PDX provided a reliable predictive tool to anticipate the effect of treatment on tumors, in that case, to assess resistance to cisplatin in breast tumors. The limit for this approach is the amount of time necessary to grow the PDX, amounting to several weeks in mice, to be added to the time necessary for drug screening.…”

Section: Discussionmentioning

confidence: 99%

Evaluating immune response in vitro in a relevant microenvironment: a high-throughput microfluidic model for clinical screening

Doffe

Fuoco

Michels

et al. 2022

Exploration of Targeted Anti-Tumor Therapy

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Aim: Functional screening of new pharmaceutical compounds requires clinically relevant models to monitor essential cellular and immune responses during cancer progression, with or without treatment. Beyond survival, the emergence of resistant tumor cell clones should also be considered, including specific properties related to plasticity, such as invasiveness, stemness, escape from programmed cell death, and immune response. Numerous pathways are involved in these processes. Defining the relevant ones in the context of a specific tumor type will be key to designing an appropriate combination of inhibitors. However, the diversity and potential redundancy of these pathways remain a challenge for therapy. Methods: A new microfluidic device developed by Okomera was dedicated to the screening of drug treatment for breast cancer. This microchip includes 150 droplet-trapping microwells, offering multi-chip settings and multiple treatment choices. Results: After validating the system with established cell lines and a panel of drugs used clinically at Gustave Roussy, preclinical experiments were initiated including patient-derived xenograft (PDX) and primary tumor cells-derived tumoroids with the collaboration of Gustave Roussy clinicians. Tumor-isolated lymphocytes were also added to the tumoroids, using secondary droplets in proof-of-concept experiments. Conclusions: These results show the relevance of the methodology for screening large numbers of drugs, a wide range of doses, and multiple drug combinations. This methodology will be used for two purposes: 1) new drug screening from the compound library, using the high throughput potential of the chip; and 2) pre-clinical assay for a two-weeks response for personalized medicine, allowing evaluation of drug combinations to flag an optimized treatment with potential clinical application.

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Section: Discussionmentioning

confidence: 99%

Evaluating immune response in vitro in a relevant microenvironment: a high-throughput microfluidic model for clinical screening

Doffe

Fuoco

Michels

et al. 2022

Exploration of Targeted Anti-Tumor Therapy

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“…We acquired the BIOND organ-on.chip system (inCHIPit™ and comPLATE™) (BIOND Solutions B.V., Delft, The Netherlands). The inCHIPit™ is produced using polydimethylsiloxane film supported by a silicon frame, and consists of a culture chamber that communicates with the underlying three 400 µM-wide channels through 4 µM-wide pores 25 To generate flow, chips are placed on the comPLATE™ and this is connected to a pressure pump that generates 800 mbar of pressure, and pumps circulating medium from the reservoir through the tubing and towards the chip channels, producing an estimated flow rate across the porous membrane of 0.2 µL/min. The system allows to maintain a constant flow thanks to the pressure regulator placed in the system, which ensures continuous fresh medium and stable shear stress.…”

Section: Methodsmentioning

confidence: 99%

Creating a kidney organoid-vasculature interaction model using a novel organ-on-chip system

Menéndez

Bosch

et al. 2022

Sci Rep

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Kidney organoids derived from human induced pluripotent stem cells (iPSCs) have proven to be a valuable tool to study kidney development and disease. However, the lack of vascularization of these organoids often leads to insufficient oxygen and nutrient supply. Vascularization has previously been achieved by implantation into animal models, however, the vasculature arises largely from animal host tissue. Our aim is to transition from an in vivo implantation model towards an in vitro model that fulfils the advantages of vascularization whilst being fully human-cell derived. Our chip system supported culturing of kidney organoids, which presented nephron structures. We also showed that organoids cultured on chip showed increased maturation of endothelial populations based on a colocalization analysis of endothelial markers. Moreover, we observed migration and proliferation of human umbilical vein endothelial cells (HUVECs) cultured in the channels of the chip inside the organoid tissue, where these HUVECs interconnected with endogenous endothelial cells and formed structures presenting an open lumen resembling vessels. Our results establish for the first-time vascularization of kidney organoids in HUVEC co-culture conditions using a microfluidic organ-on-chip. Our model therefore provides a useful insight into kidney organoid vascularization in vitro and presents a tool for further studies of kidney development and drug testing, both for research purposes and pre-clinical applications.

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“…We also confirmed that in vivo responses were mimicked in the OoC device: cisplatin sensitivity in the device was consistent the in vivo characteristics of breast cancer PDX models (Fig. 4), and androgendependent prostate tumors were sensitive to the anti-androgen apalutamide (Chakrabarty et al, 2022).…”

Section: Commentary Background Informationmentioning

confidence: 99%

Establishing a Microfluidic Tumor Slice Culture Platform to Study Drug Response

2023

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Accurate models for tumor biology and prediction of drug responses of individual tumors require novel technology to grow tumor tissue ex vivo to maintain tumor growth characteristics in situ. Models containing only tumor cells, without the stromal components of the tumor, are suboptimal for many purposes and are generally problematic because the cells are passed through extensive culture and selection. Therefore, direct culture of (human) tumors is of considerable interest for basic tumor biology and diagnostic purposes. Microfluidic technologies have been proposed to accurately mimic physiological conditions for tissue growth. Most published systems build tissues from individual cell types in so-called Organ-on-Chip (OoC) cultures. We here describe a novel OoC device for growing tumor specimens. Thin tumor slices are grown in a microfluidic 'chip' that allows precisely controlled in vitro culture conditions. The performance of the OoC device was extensively validated for predicting therapeutic responses in human breast cancer patient-derived xenograft (PDX) tumor material. The system is amenable to primary tumor material from surgery or biopsies. In addition to using the model to predict and evaluate therapeutic responses, the model can also be used for mechanistic studies of human cancers, such as clonal evolution or immune responses, or to validate new or repurposed (cancer) drugs. The Bi/ond Cancer-on-Chip (CoC) device is designed to culture tumor slices and investigate aspects of tumor growth and drug responses. Here, we describe the step-by-step process of setting up tumor slice cultures using a Bi/ond CoC device and performing in vitro drug response evaluation.

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A Microfluidic Cancer-on-Chip Platform Predicts Drug Response Using Organotypic Tumor Slice Culture

Abstract: Conflictsof interest: CS, NG and WFQS are founders of BIOND Solutions B.V. (BI/OND). AO is employee of BIOND Solutions B.V. AvdS is a full-time employee of Philips Molecular Pathway Dx.

Cited by 29 publications

References 54 publications

Evaluating immune response in vitro in a relevant microenvironment: a high-throughput microfluidic model for clinical screening

Evaluating immune response in vitro in a relevant microenvironment: a high-throughput microfluidic model for clinical screening

Creating a kidney organoid-vasculature interaction model using a novel organ-on-chip system

Establishing a Microfluidic Tumor Slice Culture Platform to Study Drug Response

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