Tumor-on-a-chip platform to investigate progression and drug sensitivity in cell lines and patient-derived organoids

Shirure, Venktesh S.; Bi, Ye; Curtis, Matthew B.; Lezia, Andrew; Goedegebuure, Madeleine M.; Goedegebuure, S. Peter; Aft, Rebecca; Fields, Ryan C.; George, Steven C.

doi:10.1039/c8lc00596f

Cited by 231 publications

(192 citation statements)

References 39 publications

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“…4. Invasion parametrization: organoid characterization (e.g., shape analysis and biosensor activities) driven by microscopy for high-throughput screening, or mechanistic insights into dissemination (Shirure et al, 2018) 5. Intravital imaging: owing to a predetermined site of orthotopic xenotransplant to study this stage, intravital imaging is useful in studying early disseminating events (Ilina et al, 2018;Vennin et al, 2016) 6.…”

Section: Mechanistic Models Of Metastasis--toward Linking Mechanisms mentioning

confidence: 99%

“…Phenotypic screens of intravasation: barcoded KO libraries selected for intravasation potential (Jeon et al, 2014; Zervantonakis et al, 2012) 4. Microfluidics: approaches to mimic vasculature and lymphatics and incorporate defined mechanical parameters into observation (Shirure et al, 2018) Premetastatic niche 1. Exosomes: microvesicles secreted by cancer cells bearing microRNA and other components, which could prepare niches in other tissues for micrometastases (Costa-Silva et al, 2015;Hoshino et al, 2015) 2.…”

Section: Mechanistic Models Of Metastasis--toward Linking Mechanisms mentioning

confidence: 99%

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Systems Biology of Cancer Metastasis

et al. 2019

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Cancer metastasis is no longer viewed as a linear cascade of events but rather as a series of concurrent, partially overlapping processes, as successfully metastasizing cells assume new phenotypes while jettisoning older behaviors. The lack of a systemic understanding of this complex phenomenon has limited progress in developing treatments for metastatic disease. Because metastasis has traditionally been investigated in distinct physiological compartments, the integration of these complex and interlinked aspects remains a challenge for both systems-level experimental and computational modeling of metastasis. Here, we present some of the current perspectives on the complexity of cancer metastasis, the multiscale nature of its progression, and a systems-level view of the processes underlying the invasive spread of cancer cells. We also highlight the gaps in our current understanding of cancer metastasis as well as insights emerging from interdisciplinary systems biology approaches to understand this complex phenomenon.

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Section: Mechanistic Models Of Metastasis--toward Linking Mechanisms mentioning

confidence: 99%

Section: Mechanistic Models Of Metastasis--toward Linking Mechanisms mentioning

confidence: 99%

Systems Biology of Cancer Metastasis

et al. 2019

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“…We expected vessels cultured in this system would synapse with these pores, similar to previously published findings 7 . Further, because one media line was supplied with more media than the other, a subtle intermittent hydrostatic pressure across the central tissue culture chamber (from high media reservoir to low) was created, as reported earlier 18 . Interstitial pressure is an important mechanobiologic stimulus experienced by vasculature in vivo, and microfluidic culture captures this ex vivo in ways static culture cannot.…”

Section: Resultsmentioning

confidence: 98%

Patient-derived small intestinal myofibroblasts direct perfused, physiologically responsive capillary development in a microfluidic Gut-on-a-Chip Model

Seiler

Bajinting

Alvarado

et al. 2020

Sci Rep

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The development and physiologic role of small intestine (SI) vasculature is poorly studied. This is partly due to a lack of targetable, organ-specific markers for in vivo studies of two critical tissue components: endothelium and stroma. This challenge is exacerbated by limitations of traditional cell culture techniques, which fail to recapitulate mechanobiologic stimuli known to affect vessel development. Here, we construct and characterize a 3D in vitro microfluidic model that supports the growth of patient-derived intestinal subepithelial myofibroblasts (ISEMFs) and endothelial cells (ECs) into perfused capillary networks. We report how ISEMF and EC-derived vasculature responds to physiologic parameters such as oxygen tension, cell density, growth factors, and pharmacotherapy with an antineoplastic agent (Erlotinib). Finally, we demonstrate effects of ISEMF and EC co-culture on patientderived human intestinal epithelial cells (HIECs), and incorporate perfused vasculature into a gut-ona-chip (GOC) model that includes HIECs. Overall, we demonstrate that ISEMFs possess angiogenic properties as evidenced by their ability to reliably, reproducibly, and quantifiably facilitate development of perfused vasculature in a microfluidic system. We furthermore demonstrate the feasibility of including perfused vasculature, including ISEMFs, as critical components of a novel, patient-derived, GOC system with translational relevance as a platform for precision and personalized medicine research. Blood vessels supply oxygen and nutrients needed to sustain life. As such, their structure and response to physiological stimuli are crucial to nearly all aspects of human biology. This includes normal developmental and pathological conditions affecting the SI such as short gut syndrome, inflammatory bowel disease, and cancer 1-6 .

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“…However, most of these MCTSs lack endothelial and stromal cells, which play an important role in aggressive behaviours of tumour cells, such as angiogenesis and invasion [15]. Recently, microfluidic devices have been developed to recapitulate TME with perfusable vascular networks that exhibit angiogenesis [16][17][18][19]. However, because microfluidic devices are difficult to mass-produce, and their liquid handling for cell culture and drug testing in the devices is relatively complicated compared to those in microwell plates, their use in high-throughput screening (HTS) of anticancer drug efficacy is limited.…”

Section: Introductionmentioning

confidence: 99%

3D Bioprinted Vascularized Tumour for Drug Testing

Han

Kim

Chen

et al. 2020

IJMS

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An in vitro screening system for anti-cancer drugs cannot exactly reflect the efficacy of drugs in vivo, without mimicking the tumour microenvironment (TME), which comprises cancer cells interacting with blood vessels and fibroblasts. Additionally, the tumour size should be controlled to obtain reliable and quantitative drug responses. Herein, we report a bioprinting method for recapitulating the TME with a controllable spheroid size. The TME was constructed by printing a blood vessel layer consisting of fibroblasts and endothelial cells in gelatine, alginate, and fibrinogen, followed by seeding multicellular tumour spheroids (MCTSs) of glioblastoma cells (U87 MG) onto the blood vessel layer. Under MCTSs, sprouts of blood vessels were generated and surrounding MCTSs thereby increasing the spheroid size. The combined treatment involving the anti-cancer drug temozolomide (TMZ) and the angiogenic inhibitor sunitinib was more effective than TMZ alone for MCTSs surrounded by blood vessels, which indicates the feasibility of the TME for in vitro testing of drug efficacy. These results suggest that the bioprinted vascularized tumour is highly useful for understanding tumour biology, as well as for in vitro drug testing.

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Tumor-on-a-chip platform to investigate progression and drug sensitivity in cell lines and patient-derived organoids

Abstract: We created a tumor platform to study cell proliferation, angiogenesis, migration, intravasation, and treatments.

Cited by 231 publications

References 39 publications

Systems Biology of Cancer Metastasis

Systems Biology of Cancer Metastasis

Patient-derived small intestinal myofibroblasts direct perfused, physiologically responsive capillary development in a microfluidic Gut-on-a-Chip Model

3D Bioprinted Vascularized Tumour for Drug Testing

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