Preserved genetic diversity in organoids cultured from biopsies of human colorectal cancer metastases

Abstract

Tumor organoids are 3D cultures of cancer cells. They can be derived from the tumor of each individual patient, thereby providing an attractive ex vivo assay to tailor treatment. Using patient-derived tumor organoids for this purpose requires that organoids derived from biopsies maintain the genetic diversity of the in vivo tumor. In this study tumor biopsies were obtained from 14 patients with metastatic colorectal cancer (i) to test the feasibility of organoid culture from metastatic biopsy specimens and (ii) to compare the genetic diversity of patient-derived tumor organoids and the original tumor biopsy. Genetic analysis was performed using SOLiD sequencing for 1,977 cancer-relevant genes. Copy number profiles were generated from sequencing data using CopywriteR. Here we demonstrate that organoid cultures can be established from tumor biopsies of patients with metastatic colorectal cancer with a success rate of 71%. Genetic analysis showed that organoids reflect the metastasis from which they were derived. Ninety percent of somatic mutations were shared between organoids and biopsies from the same patient, and the DNA copy number profiles of organoids and the corresponding original tumor show a correlation of 0.89. Most importantly, none of the mutations that were found exclusively in either the tumor or organoid culture are in driver genes or genes amenable for drug targeting. These findings support further exploration of patient-derived organoids as an ex vivo platform to personalize anticancer treatment.biopsy-derived tumor organoids | colorectal cancer | DNA sequencing | copy number analysis | personalized medicine

Intestinal Enteroids Model Guanylate Cyclase C-Dependent Secretion Induced by Heat-Stable Enterotoxins

“…Moreover, GUCY2C paracrine signaling defends the intestinal barrier, and its disruption contributes to inflammatory bowel disease (41)(42)(43). Expression of the complete GUCY2C hormone axis, and the recent development of enteroid platforms from transformed epithelia (44) and organoid systems integrating epithelial and mesenchymal components (45), offer a unique opportunity to couple mechanistic discovery and high-throughput drug development in ex vivo human models that address these diverse areas of an unmet therapeutic need.…”

Translational applications of adult stem cell-derived organoids

“…Thus, it remains important to establish cultures from (nearly) pure tumor samples. So far, tumor organoids have also been generated from colon (Weeber et al, 2015) and prostate Gao et al, 2014) cancer metastases, prostate cancer circulating tumor cells Gao et al, 2014) and primary pancreatic tumors (Boj et al, 2015). Using these approaches, living tumor organoid biobanks have been established from patient-derived tumor tissue.…”

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“…Patient-specific tumoroid response profiles have been established in relation to their genomic profiles following high-throughput screening against cytotoxic drug libraries [3,4]. Clinical trials are currently ongoing to determine whether this approach can prognosticate treatment outcome of pancreatic, liver and colorectal cancer patients [5,6]. Interestingly, tumoroid cultures also maintain the tumor heterogeneity of the tumor-of-origin and since normal surrounding tissues can be established in addition with little modification to the culture media, a patient disease-specific genomic or proteomic tumor profile can be established in relation to the normal tissue from which the tumor arose [5,7].…”

“…Clinical trials are currently ongoing to determine whether this approach can prognosticate treatment outcome of pancreatic, liver and colorectal cancer patients [5,6]. Interestingly, tumoroid cultures also maintain the tumor heterogeneity of the tumor-of-origin and since normal surrounding tissues can be established in addition with little modification to the culture media, a patient disease-specific genomic or proteomic tumor profile can be established in relation to the normal tissue from which the tumor arose [5,7]. Tumoroid cultures can also be implanted orthotopically in immunodeficient mice to address the impact of diseasespecific driver genes and their impact on the tumoroid's capacity to metastasize to distant organs [8].…”