A rectal cancer organoid platform to study individual responses to chemoradiation

Ganesh, Karuna; Wu, Chao; O’Rourke, Kevin P.; Szeglin, Bryan; Zheng, Youyun; Sauvé, Charles Etienne Gabriel; Adileh, Mohammad; Wasserman, Isaac; Marco, Michael R.; Kim, Amanda S.; Shady, Maha; Sánchez-Vega, Francisco; Karthaus, Wouter R.; Won, Helen; Choi, Seo Hyun; Pelossof, Raphael; Barlas, Afsar; Ntiamoah, Peter; Pappou, Emmanouil P.; Elghouayel, Arthur E.; Strong, James S.; Chen, Chin Tung; Harris, Jennifer W.; Weiser, Martin R.; Nash, Garrett M.; Guillem, José G.; Wei, Iris; Kolesnick, Richard; Veeraraghavan, Harini; Ortiz, Eduardo J.; Petkovska, Iva; Cercek, Andrea; Manova‐Todorova, Katia; Saltz, Leonard; Lavery, Jessica A.; DeMatteo, Ronald P.; Massagué, Joan; Paty, Philip B.; Yaeger, Rona; Chen, Xi; Patil, Sujata; Clevers, Hans; Berger, Michael F.; Lowe, Scott W.; Shia, Jinru; Romesser, Paul B.; Dow, Lukas E.; García-Aguilar, Julio; Sawyers, Charles L.; Smith, J. Joshua

doi:10.1038/s41591-019-0584-2

Cited by 393 publications

(434 citation statements)

References 42 publications

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“…For the 5FU and FOLFIRI treatments in 3D setting, N and T scaffolds were repopulated with 2.5 × 10 5 HT29 and HCT116 cells in 24-well plates. The FOLFIRI chemotherapy cocktail ratio used was as follows: 5FU:leucovorin:irinotecan, 25:5:1 [52]. Five days post-seeding, the cells were treated with 1 µM, 10 µM, and 100 µM 5FU for 72 h. For the 5FU treatment of 2D cultures, HT29 and HCT116 were seeded at 5 × 10 3 cells per well in 96-well plates and treated with different concentrations of 5FU from 0.1 µM to 100 µM for 72 h. Cell viability was determined 24 h, 48 h, and 72 h post-treatment by reading the absorbance using the Multilabel Plate Reader VICTOR (PerkinElmer, Waltham, MA, USA).…”

Section: Drug Treatment and Cytotoxicity Assaymentioning

confidence: 99%

Recellularized Colorectal Cancer Patient-Derived Scaffolds as In Vitro Pre-Clinical 3D Model for Drug Screening

Sensi

D’Angelo

Piccoli

et al. 2020

Cancers

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Colorectal cancer (CRC) shows highly ineffective therapeutic management. An urgent unmet need is the random assignment to adjuvant chemotherapy of high-risk stage II and stage III CRC patients without any predictive factor of efficacy. In the field of drug discovery, a critical step is the preclinical evaluation of drug cytotoxicity, efficacy, and efficiency. We proposed a patient-derived 3D preclinical model for drug evaluation that could mimic in vitro the patient’s disease. Surgically resected CRC tissue and adjacent healthy colon mucosa were decellularized by a detergent-enzymatic treatment. Scaffolds were recellularized with HT29 and HCT116 cells. Qualitative and quantitative characterization of matched recellularized samples were evaluated through histology, immunofluorescences, scanning electron microscopy, and DNA amount quantification. A chemosensitivity test was performed using an increasing concentration of 5-fluorouracil (5FU). In vivo studies were carried out using zebrafish (Danio rerio) animal model. Permeability test and drug absorption were also determined. The decellularization protocol allowed the preservation of the original structure and ultrastructure. Five days after recellularization with HT29 and HCT116 cell lines, the 3D CRC model exhibited reduced sensitivity to 5FU treatments compared with conventional 2D cultures. Calculated the half maximal inhibitory concentration (IC50) for HT29 treated with 5FU resulted in 11.5 µM in 3D and 1.3 µM in 2D, and for HCT116, 9.87 µM in 3D and 1.7 µM in 2D. In xenograft experiments, HT29 extravasation was detected after 4 days post-injection, and we obtained a 5FU IC50 fully comparable to that observed in the 3D CRC model. Using confocal microscopy, we demonstrated that the drug diffused through the repopulated 3D CRC scaffolds and co-localized with the cell nuclei. The bioengineered CRC 3D model could be a reliable preclinical patient-specific platform to bridge the gap between in vitro and in vivo drug testing assays and provide effective cancer treatment.

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Section: Drug Treatment and Cytotoxicity Assaymentioning

confidence: 99%

Recellularized Colorectal Cancer Patient-Derived Scaffolds as In Vitro Pre-Clinical 3D Model for Drug Screening

Sensi

D’Angelo

Piccoli

et al. 2020

Cancers

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“… 65 Two studies used epithelial organoids derived from patients with rectal cancer to investigate clinical guideline-based chemoradiation treatment. 66 , 67 Both groups concluded that patient-derived organoids reliably predicted the primary tumor response, providing hope that organoids will provide a novel way to better individualize a patient’s treatment regimen.…”

Section: Methodsmentioning

confidence: 99%

Organoid Models of Colorectal Pathology: Do They Hold the Key to Personalized Medicine? A Systematic Review

DeHaan

Sarvestani

Huang

2020

Diseases of the Colon &Amp; Rectum

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“…Using these parameters, the in vitro responses could predict clinical responses with an impressive area under the curve (AUC) of 0.88 and an accuracy of 84%. In the other study, Ganesh and colleagues (Ganesh et al 2019 ) established 65 PDO lines from rectal cancer to test responses to neoadjuvant chemoradiation therapy, including the standard FOLFOX chemotherapy and radiation. The PDO responses significantly reflected the patients’ progression-free survival.…”

Section: Organoids For Translational Researchmentioning

confidence: 99%

Organoid based personalized medicine: from bench to bedside

Tang

Cai

et al. 2020

Cell Regen

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Three-dimensional cultured organoids have become a powerful in vitro research tool that preserves genetic, phenotypic and behavioral trait of in vivo organs, which can be established from both pluripotent stem cells and adult stem cells. Organoids derived from adult stem cells can be established directly from diseased epithelium and matched normal tissues, and organoids can also be genetically manipulated by CRISPR-Cas9 technology. Applications of organoids in basic research involve the modeling of human development and diseases, including genetic, infectious and malignant diseases. Importantly, accumulating evidence suggests that biobanks of patient-derived organoids for many cancers and cystic fibrosis have great value for drug development and personalized medicine. In addition, organoids hold promise for regenerative medicine. In the present review, we discuss the applications of organoids in the basic and translational research.

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A rectal cancer organoid platform to study individual responses to chemoradiation

Cited by 393 publications

References 42 publications

Recellularized Colorectal Cancer Patient-Derived Scaffolds as In Vitro Pre-Clinical 3D Model for Drug Screening

Recellularized Colorectal Cancer Patient-Derived Scaffolds as In Vitro Pre-Clinical 3D Model for Drug Screening

Organoid Models of Colorectal Pathology: Do They Hold the Key to Personalized Medicine? A Systematic Review

Organoid based personalized medicine: from bench to bedside

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