Generation of an in vitro 3D Engineered Colorectal Cancer Patient-Derived Xenograft Model
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE151069 | GEO | 2020/05/23
REPOSITORIES: GEO
Similar Datasets
Project description:Generation of an in vitro 3D Engineered Colorectal Cancer Patient-Derived Xenograft Model
| PRJNA634542 | ENA
Project description:Transcriptome levels of matched patient-derived xenograft (PDX) in vitro-in vivo models.
2018-01-31 | GSE109903 | GEO
Project description:Colorectal cancer (CRC) is a heterogeneous disease classified into four consensus molecular subtype (CMSs) with distinct biological and clinical features. This study aims to understand the value of patient-derived xenografts (PDXs) in relation to these CMSs. A total of 42 primary tumors, recurrences and metastases were used to develop PDXs. Detailed genetic analyses were performed on PDXs and corresponding patient tumors to determine relationship and PDX heterogeneity. Out of 42 tumors 22 (52%) showed successfully PDX engraftment, which was biased towards metastases and CMS1 and CMS4 tumors. Importantly, gene expression analysis revealed a clinical relevant association between an engraftment gene signature and prognosis for stage II patients. Moreover, this gene signature revealed an association between Src pathway activation and positive engraftment. Src pathway activity co-aligned with CMS4 and the levels of fibronectin in tumors and was confirmed by pSrc immunohistochemistry. From this analysis we further deduced that decreased cell cycle activity is a prognostic factor for successful engraftment and related to patient prognosis. However, this is not a general phenomenon, but subtype specific as decreased cell cycle activity was highly prognostic for recurrence-free survival within CMS2 but not in CMS1 and CMS4, while it showed an inverse correlation in CMS3. These data illustrate that CRC PDX establishment is biased toward CMS1 and CMS4, which impacts translation of results derived from pre-clinical studies using PDXs. Moreover, our analysis reveals subtype-specific features, pSrc in CMS4 and low Ki67 in CMS2, which provide novel avenues for therapy and diagnosis.
2018-10-16 | GSE103340 | GEO
Project description:Purpose: Next-generation sequencing (NGS) has revolutionized systems-based analysis of cellular pathways. The goals of this study are to compare the epigenomes of different patient-derived models of colorectal cancer (PDO, PDX and PDOX) to the original patient tumor. Methods: The Omni-ATAC protocol was utilized for ATAC library preparations. The nulcei were extracted from samples (PT, PDO, PDX and PDOX). For each sample set, three biological replicates were included. The libraries were sequenced using Illumina HiSeq 4000 PE 150bp. Results: Using an optimized data analysis workflow, we achieved high quality ATAC-seq library. Data were mapped to hg19 with over 90% mapping rate, and relative low mitochondria fraction (<30%). We used Diffbind to assess the chromatin accessibility enrichment in each model with a strict threshold of p <0.05 and |logFC|>1. Conclusions: Our study represents the first detailed analysis of CRC PDMC epigenome. CRC cells from all three models share chromatin alterations when compared to PT cells, representing a PT-PDMC epigenetic axis. Chromatin alterations in CRC cells are more similar betweeen PDOX and PDX than between PDOX and PDO, indicating that the growth environment of the model exerts strong influence on chraomtin adaptation in tumor cells.
2024-03-01 | GSE184482 | GEO
Project description:The therapeutic landscape of melanoma is rapidly changing. While targeted inhibitors yield significant responses, their clinical benefit is often limited by the early onset of drug resistance. This motivates the pursuit to establish more durable clinical responses, by developing combinatorial therapies. But while potential new combinatorial targets steadily increase in numbers, they cannot possibly all be tested in patients. Similarly, while genetically engineered mouse melanoma models have great merit, they do not capture the enormous genetic diversity and heterogeneity typical in human melanoma. Furthermore, whereas in vitro studies have many advantages, they lack the presence of micro-environmental factors, which can have a profound impact on tumor progression and therapy response. This prompted us to develop an in vivo model for human melanoma that allows for studying the dynamics of tumor progression and drug response, with concurrent evaluation and optimization of new treatment regimens. Here, we present a collection of patient-derived xenografts (PDX), derived from BRAFV600E, NRASQ61 or BRAFWT/NRASWT melanoma metastases. The BRAFV600E PDX melanomas were acquired both prior to treatment with the BRAF inhibitor vemurafenib and after resistance had occurred, including six matched pairs. We find that PDX resemble their human donors’ melanomas regarding biomarkers, chromosomal aberrations, RNA expression profiles, mutational spectrum and targeted drug resistance patterns. Mutations, previously identified to cause resistance to BRAF inhibitors, are captured in PDX derived from resistant melanomThis melanoma PDX platform represents a comprehensive public resource to study both fundamental and translational aspects of melanoma progression and treatment in a physiologically relevant setting.
2016-05-27 | GSE73737 | GEO
Project description:The therapeutic landscape of melanoma is rapidly changing. While targeted inhibitors yield significant responses, their clinical benefit is often limited by the early onset of drug resistance. This motivates the pursuit to establish more durable clinical responses, by developing combinatorial therapies. But while potential new combinatorial targets steadily increase in numbers, they cannot possibly all be tested in patients. Similarly, while genetically engineered mouse melanoma models have great merit, they do not capture the enormous genetic diversity and heterogeneity typical in human melanoma. Furthermore, whereas in vitro studies have many advantages, they lack the presence of micro-environmental factors, which can have a profound impact on tumor progression and therapy response. This prompted us to develop an in vivo model for human melanoma that allows for studying the dynamics of tumor progression and drug response, with concurrent evaluation and optimization of new treatment regimens. Here, we present a collection of patient-derived xenografts (PDX), derived from BRAFV600E, NRASQ61 or BRAFWT/NRASWT melanoma metastases. The BRAFV600E PDX melanomas were acquired both prior to treatment with the BRAF inhibitor vemurafenib and after resistance had occurred, including six matched pairs. We find that PDX resemble their human donors’ melanomas regarding biomarkers, chromosomal aberrations, RNA expression profiles, mutational spectrum and targeted drug resistance patterns. Mutations, previously identified to cause resistance to BRAF inhibitors, are captured in PDX derived from resistant melanomThis melanoma PDX platform represents a comprehensive public resource to study both fundamental and translational aspects of melanoma progression and treatment in a physiologically relevant setting.
2016-05-27 | GSE66539 | GEO
Project description:Colorectal cancer (CRC) is a highly heterogeneous disease both from a molecular and clinical perspective. Several distinct molecular entities, such as microsatellite instability (MSI), have been defined that make up biologically distinct subgroups with their own clinical course. Recent data indicated that CRC can be best segregated into four groups called Consensus Molecular Subtypes (CMS1-4), which each have a unique biology and gene expression pattern. In order to develop improved, subtype-specific therapies and to gain insight into the molecular wiring and origin of these subtypes, reliable models are needed. This study was designed to determine the heterogeneity and identify the presence of CMSs in a large panel of CRC cell lines, primary cultures and patient-derived xenografts (PDX). We provide a repository encompassing this heterogeneity and moreover describe that a large part of the models can be robustly assigned to one of the four CMSs, independent of the stromal contribution. We subsequently validate our CMS stratification by functional analysis which for instance shows mesenchymal enrichment in CMS4 and metabolic dysregulation in CMS3. Finally, we observe a clear difference in sensitivity to chemotherapy-induced apoptosis, specifically between CMS2 and CMS4. This relates to the in vivo efficacy of chemotherapy, which delays outgrowth of CMS2, but not CMS4 xenografts. This indicates that molecular subtypes are faithfully modelled in the CRC cell cultures and PDXs, representing tumour cell intrinsic and stable features. This repository provides researchers with a platform to study CRC using the existing heterogeneity.
2017-12-01 | GSE100480 | GEO
Project description:The development of physiologically relevantin vitrocolorectal cancer (CRC) models is vital for advancing understanding of tumor biology. Although CRC patient-derived xenografts (PDXs) recapitulate key patient tumor characteristics and demonstrate high concordance with clinical outcomes, the use of thisin vivomodel is costly and low-throughput. Here we report the establishment and in-depth characterization of anin vitrotissue-engineered CRC model using PDX cells. To form the 3D engineered CRC-PDX (3D-eCRC-PDX) tissues, CRC PDX tumors were expandedin vivo, dissociated, and the isolated cells encapsulated within PEG-fibrinogen hydrogels. Following PEG-fibrinogen encapsulation, cells remain viable and proliferate within 3D-eCRC-PDX tissues. Tumor cell subpopulations, including human cancer and mouse stromal cells, are maintained in long-term culture (29 days); cellular subpopulations increase ratiometrically over time. The 3D-eCRC-PDX tissues mimic the mechanical stiffness of originating tumors. Extracellular matrix protein production by cells in the 3D-eCRC-PDX tissues resulted in approximately 57% of proteins observed in the CRC-PDX tumors also being present in the 3D-eCRC-PDX tissues on day 22. Furthermore, we show congruence in enriched gene ontology molecular functions and Hallmark gene sets in 3D-eCRC-PDX tissues and CRC-PDX tumors compared to normal colon tissue, while prognostic Kaplan-Meier plots for overall and relapse free survival did not reveal significant differences between CRC-PDX tumors and 3D-eCRC-PDX tissues. Our results demonstrate high batch-to-batch consistency and strong correlation between ourin vitrotissue-engineered PDX-CRC model and the originatingin vivoPDX tumors, providing a foundation for future studies of disease progression and tumorigenic mechanisms.
| S-EPMC9822569 | biostudies-literature
Project description:Mass spectrometry profiling of orthotopically transplanted breast cancer patient-derived xenograft (PDX) tumors prior to chemotherapy treatment.
2022-12-06 | PXD035857 | Pride
Project description:To characterize the transcriptional changes in PDX tumors during TREM1 inhibition by microarray
2023-09-27 | E-MTAB-13257 | biostudies-arrayexpress