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Project description:Cholangiocarcinoma (CC) is an aggressive malignancy with an inferior prognosis due to limited systemic treatment options. As preclinical models such as CC cell lines are extremely rare, this manuscript reports a protocol of cholangiocarcinoma patient-derived organoid culture as well as a protocol for the transition of 3D organoid lines to 2D cell lines. Tissue samples of non-cancer bile duct and cholangiocarcinoma were obtained during surgical resection. Organoid lines were generated following a standardized protocol. 2D cell lines were generated from established organoid lines following a novel protocol. Subcutaneous and orthotopic patient-derived xenografts were generated from CC organoid lines, histologically examined, and treated using standard CC protocols. Therapeutic responses of organoids and 2D cell lines were examined using standard CC agents. Next-generation exome and RNA sequencing was performed on primary tumors and CC organoid lines. Patient-derived organoids closely recapitulated the original features of the primary tumors on multiple levels. Treatment experiments demonstrated that patient-derived organoids of cholangiocarcinoma and organoid-derived xenografts can be used for the evaluation of novel treatments and may therefore be used in personalized oncology approaches. In summary, this study establishes cholangiocarcinoma organoids and organoid-derived cell lines, thus expanding translational research resources of cholangiocarcinoma.
| S-EPMC8395494 | biostudies-literature
Project description:Interventions: case series:Nil
Primary outcome(s): pdo modeling success rate(%)
Study Design: Sequential
| 2734714 | ecrin-mdr-crc
Project description:We profiled gene expression in formalin-fixed, paraffin-embedded (FFPE) patient’s tumor biopsy sample, obtained at the time of the first CCA diagnosis. We next used bioinformatical software Oncobox to analyze gene expression data and to identify molecular pathways differentially regulated in the patient’s tumor sample.
2017-11-22 | GSE107233 | GEO
Project description:Precision oncology aims to improve clinical outcome of patients by offering personalized treatment through identifying druggable genomic aberrations within their tumors. This is particularly valid when it comes to offering alternative treatment options for patients with advanced tumors that are chemo-refractory. Patient-derived organoids (PDOs) are 3 dimensional tumoroids that can be expanded ex vivo and are both pheno- and genotypically identical to patients’ tumors. Observational studies have shown that PDO-based drug screens can predict treatment response with high sensitivity and specificity. Vlachogiannis G. reported a living biobank of patient-derived organoids (PDOs) from patients with advanced GI cancers enrolled in clinical trials. PDOs can recapitulate patients’ clinical response to chemotherapeutic agents. In 19 tumor organoids, the group performed molecular profiling and drug screens and then compared ex vivo organoid responses to anticancer drugs. Drug response to PDO based orthotopic mouse tumor xenografts correlated to the drug response of the patient in clinical trials. Further to the study, there were other retrospective validation studies utilizing PDOs from patients enrolled in clinical trials such as the TUMOROID, CinClare to predict clinical response. Ooft studied PDOs from patients with metastatic colorectal cancers enrolled in the TUMOROID study to predict response to irinotecan-based therapies. Yao generated a organoid biobank of 80 locally advanced rectal cancers. These patients were derived from a phase III study (CinClare) that compared neoadjuvant chemo-radiation using either capecitabine or CAPIRI. Response to chemoradiation in patients matched to that of rectal cancer organoids (sensitivity 78% and specificity 91.9%). In a systematic analysis of 17 studies (9 on advanced GI and pancreatic cancers, one on renal cell cancer and others on miscellaneous cancers), the pooled sensitivity and specificity for discriminating patients with a clinical response through PDO-based drug screen was 0.81 (95%CI 0.69-0.89) and 0.74 (95%CI 0.64-0.82) respectively. Within 4-6 weeks, PDO-based drug screen creates a true personalised platform by predicting patient-specific drug response with high accuracy. Recent technical advancements in growing these PDO ‘avatars’ from biopsies have made it possible to test suitable anticancer drugs in patients with advanced inoperable tumors, and explore the new possibilities for treatment options that otherwise would be missed by standard conventional therapies. In 2019, our group embarked on PDO research; investigators obtained tissues from patients with advanced/ inoperable solid tumors, and performing drug screens on these PDOs ex vivo. In several patients, investigators were able to identified drugs not otherwise used through sequencing data, and observed remarkable clinical response in patients with PDO responsive tumors. Investigators illustrate with cases that underwent PDO culture and drug screens. [ See appendix ] In the literature, the clinical utility of treatment based on PDO informed drug options has however not been fully established. Investigators therefore propose a phase 2 proof-of-concept clinical trial to evaluate efficacy of NGS/ PDO guided treatment in patients with inoperable or metastatic solid tumors..
| 109308 | ecrin-mdr-crc
Project description:Purpose: Identifying therapeutic targets for Signet Ring Cell Carcinoma (SRCC) of the colon and rectum is a clinical challenge due to the lack of Patient-Derived Organoids (PDO) or Xenografts (PDX). We present a robust method to establish PDO and PDX models to address this unmet need. We demonstrate that these models identify novel therapeutic strategies targeting therapy resistance and peritoneal metastasis. Experimental Design: We derived nine PDO and PDX models from colorectal SRCC patients. Detailed histopathological characterization confirmed the fidelity of these models to the original tumors. Drug sensitivity assays were conducted in vitro and in vivo to assess therapeutic efficacy and impact on peritoneal metastasis. An RNA-seq analysis was performed to identify critical pathways contributing to therapy resistance and metastatic progression. Results: We successfully developed and characterized PDO and PDX models from nine SRCC patients. The SRCC PDO and PDX models exhibited histopathological features consistent with the original tumors, including high mucin content and eccentric nuclei. They demonstrated increased sensitivity to FOLFIRI combined with paclitaxel or vincristine, reducing peritoneal metastasis. RNA-seq analysis revealed the upregulation of autophagy genes in SRCC. Treatment with chloroquine alone resulted in decreased tumor growth and peritoneal metastasis. Conclusions: Our study establishes PDO and PDX models as robust platforms for studying SRCC and identifying potential therapeutic strategies. Combining FOLFIRI with paclitaxel/ vincristine or chloroquine alone inhibits tumor growth and prevents peritoneal metastasis, showing promise for clinical translation. These findings suggest that combining FOLFIRI with IP paclitaxel warrants further investigation in Phase I clinical trials for SRCC patients. These model systems offer a valuable tool to uncover new treatments for these aggressive and therapy-resistant tumors.
2025-01-22 | GSE279979 | GEO
Project description:Approximately 50% of patients with surgically resected early-stage lung cancer develop distant metastasis. At present, there is no in vivo metastasis model to investigate the biology of human lung cancer metastases. Using well-characterized patient-derived organoids (PDOs) from patients with lung adenocarcinoma (LUAD), we establish an in vivo metastasis model that preserves the biologic features of human LUAD metastases. Results of whole-genome and RNA sequencing performed in this study establish that our in vivo PDO metastasis model can be used to study clonality and tumor evolution and to identify biomarkers related to organotropism. Investigation of the response of KRASG12C PDOs to Sotorasib demonstrates that the model can examine the efficacy of treatments to suppress metastasis and identify mechanisms of drug resistance. Finally, our PDO model cocultured with autologous peripheral blood mononuclear cells can potentially be used to determine the optimal immune-priming strategy for individual patients with LUAD.
2024-09-12 | GSE276387 | GEO
Project description:Analysis of expression changes between colon tumors (Duke's stage II) and matching colon mucosa tissues using Affymetrix GeneChip® Human Gene 2.0 ST arrays. All experiments were performed simultaneously for matching tissue samples.
2013-12-31 | E-GEOD-47074 | biostudies-arrayexpress
Project description:The human small intestine is the key organ for absorption, metabolism, and excretion of orally administered drugs. To preclinically predict these reactions in drug discovery research, a cell model that can precisely recapitulate the in vivo human intestinal monolayer is desired. In this study, we developed a monolayer platform using human biopsy-derived duodenal organoids for application to pharmacokinetic studies. The human duodenal organoid-derived monolayer was prepared by a simple method in 3-8 days. It consisted of polarized absorptive cells and had tight junctions. It showed much higher cytochrome P450 (CYP)3A4 and carboxylesterase (CES)2 activities than did the existing models (Caco-2 cells). It also showed efflux activity of P-glycoprotein (P-gp) and inducibility of CYP3A4. Finally, its gene expression profile was closer to the adult human duodenum, compared to the profile of Caco-2 cells. Based on these findings, this monolayer assay system using biopsy-derived human intestinal organoids is likely to be widely adopted.
| S-EPMC8399089 | biostudies-literature
Project description:Monitoring tumor growth dynamics is crucial for understanding cancer. To establish an in vitro method for the continuous assessment of patient-specific tumor growth, tumor organoids were generated from patients with intrahepatic CCA (iCCA). Organoid growth was monitored for 48 h by label-free live brightfield imaging. Growth kinetics were calculated and validated by MTS assay as well as immunohistochemistry of Ki67 to determine proliferation rates. We exposed iCCA organoids (iCCAOs) and non-tumor intrahepatic cholangiocyte organoids (ICOs) to sub-therapeutic concentrations of sorafenib. Monitoring the expansion rate of iCCAOs and ICOs revealed that iCCAO growth was inhibited by sorafenib in a time- and dose-dependent fashion, while ICOs were unaffected. Quantification of the proliferation marker Ki67 confirmed inhibition of iCCAO growth by roughly 50% after 48 h of treatment with 4 µM sorafenib. We established a robust analysis pipeline combining brightfield microscopy and a straightforward image processing approach for the label-free growth monitoring of patient-derived iCCAOs. Combined with bioanalytical validation, this approach is suitable for a fast and efficient high-throughput drug screening in tumor organoids to develop patient-specific systemic treatment options.
| S-EPMC9688926 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below. The reliability of differential expression analysis on FFPE expression profiles from Affymetrix arrays is questionable, due to the wide range of percent-present values reported in studies which profiled FFPE samples on Affymetrix arrays. Moreover the validity of externally defined gene-modules in FFPE microarray expression profiles is unknown. Using eight breast cancer tumors with available frozen and FFPE samples, five sample-matched data sets were generated from different combination of Affymetrix arrays, amplification-and-labeling kit and sample preservation method. The reliability of differential expression analysis was investigated by developing de novo ER/HER2 pathway gene-modules from matched data sets and validating it on external data set using ROC analysis. Spearman's rank correlation coefficient of module scores between matched FFPE-frozen expression profiles was used to measure reliability of externally defined gene-modules in FFPE expression profiles. Independent of array/amplification-kit/sample preservation method used, de novo ER/HER2 gene-modules derived from all matching data sets showed similar prediction performance during independent validation (AUC range; ER: 0.92-0.95, HER2: 0.88-0.91), except for de novo HER2 gene-module derived from FFPE data set with 3'IVT kit (AUC: 0.67-0.72). Further not all gene-module based biological signals present in frozen expression profiles can be recovered from matching FFPE microarray expression profiles using the currently available FFPE specific sample preparation kits. The gene-module based biological signal extracted from FFPE RNA, using microarrays, may not be as reliable as that from their frozen counterpart, if the sample preparation protocol used with FFPE RNA failed to recover relevant genes involved in the biological signal.
2018-09-05 | GSE93338 | GEO