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Series GSE65253 Query DataSets for GSE65253
Status Public on May 07, 2015
Title Prospective derivation of a 'Living Organoid Biobank' of colorectal cancer patients
Organism Homo sapiens
Experiment type Expression profiling by high throughput sequencing
Summary In Rspondin-based three-dimensional cultures, Lgr5 stem cells from multiple organs form ever-expanding epithelial organoids that retain their tissue identity. Here we report the establishment of tumor organoid cultures from 20 consecutive colorectal carcinoma (CRC) patients. For most, organoids were also generated from adjacent normal tissue. Organoids closely resemble the original tumor. The spectrum of genetic changes within the 'living biobank' agrees well with previous large-scale mutational analyses of CRC. Gene expression analysis indicates that the major CRC molecular subtypes are represented. Tumor organoids are amenable to high-throughput drug screens allowing detection of gene-drug associations. As an example, a single organoid culture was exquisitely sensitive to Wnt secretion (porcupine) inhibitors and carried a mutation in the negative Wnt feedback regulator RNF43, rather than in APC. Organoid technology may fill the gap between cancer genetics and patient trials, complement cell line- and xenograft-based drug studies and allow personalized therapy design.
Overall design Self-renewal of the intestinal epithelium is driven by Lgr5 stem cells located in crypts. We have recently developed a long-term culture system that maintains basic crypt physiology. Wnt signals are required for the maintenance of active crypt stem cells. Indeed, the Wnt agonist R-spondin1 induces dramatic crypt hyperplasia in vivo. R-spondin-1 is the ligand for Lgr5. Epidermal growth factor (EGF) signaling is associated with intestinal proliferation, while transgenic expression of Noggin induces a dramatic increase in crypt numbers. The combination of R-spondin-1, EGF, and Noggin in Matrigel sustains ever-expanding small intestinal organoids, which display all hallmarks of the original tissue in terms of architecture, cell type composition, and self-renewal dynamics. We adapted the culture condition for long-term expansion of human colonic epithelium and primary colonic adenocarcinoma, by adding nicotinamide, A83-01 (Alk inhibitor), Prostaglandin E2 and the p38 inhibitor SB202190. Of note, a two-dimensional culture method for cells from normal and malignant primary tissue has been described by Schlegel and colleagues. Here, we explore organoid technology to routinely establish and phenotypically annotate ‘paired organoids’ derived from adjacent tumor and healthy epithelium from CRC patients.
Contributor(s) van de Wetering M, Kester L, van Oudenaarden A, Clevers H
Citation(s) 25957691
Submission date Jan 23, 2015
Last update date May 15, 2019
Contact name Lennart Kester
Organization name Hubrecht Institute
Street address Uppsalalaan 8
City Utrecht
ZIP/Postal code 3584CT
Country Netherlands
Platforms (1)
GPL18573 Illumina NextSeq 500 (Homo sapiens)
Samples (108)
GSM1590769 Organoid 1 derived from patient 17
GSM1590770 Organoid 10 derived from patient 17
GSM1590771 Organoid 11 derived from patient 17
BioProject PRJNA273501
SRA SRP052795

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Supplementary file Size Download File type/resource
GSE65253_col_tum_org_merge.csv.gz 1.7 Mb (ftp)(http) CSV
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Raw data are available in SRA
Processed data are available on Series record

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