Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

WES of Colorectal cancer organoid-stroma biobank cohort

ABSTRACT: In colorectal cancers (CRC) the tumor microenvironment plays a key role for prognosis and therapy efficacy. Patient-derived tumor organoids (PDTOs) show enormous potential for preclinical testing, however, in purely epithelial cultures features including the Ã¢Â€Â˜consensus molecular subtypesÃ¢Â€Â™ (CMS) are largely eradicated. To better reflect cell heterogeneity, we established the CRC organoid-stroma biobank of matched PDTOs and cancer-associated fibroblasts (CAFs) from 30 patients. Context-specific phenotyping showed that xenotransplantation or co-culture with CAFs restores the individual transcriptomic status and instructs subtype-specific stromal gene expression. Furthermore, co-culture exposed CMS4-specific resistance to Gefitinib and SN-38 and revealed prognostic gene expression signatures. Chemogenomic library screening identified patient- and therapy-dependent mechanisms of stromal resistance including MET as common target. Our results demonstrate that CRC phenotypes are encrypted in the cancer epithelium in a plastic fashion that strongly depends on the context. Consequently, CAFs are essential for faithful representation of molecular subtypes and therapy responses ex vivo.

PROVIDER: EGAS00001007301 | EGA |

REPOSITORIES: EGA

ACCESS DATA

Json Xml

Similar Datasets

RNAseq of Colorectal cancer organoid-stroma biobank cohort

Project description:In colorectal cancers (CRC) the tumor microenvironment plays a key role for prognosis and therapy efficacy. Patient-derived tumor organoids (PDTOs) show enormous potential for preclinical testing, however, in purely epithelial cultures features including the Ã¢Â€Â˜consensus molecular subtypesÃ¢Â€Â™ (CMS) are largely eradicated. To better reflect cell heterogeneity, we established the CRC organoid-stroma biobank of matched PDTOs and cancer-associated fibroblasts (CAFs) from 30 patients. Context-specific phenotyping showed that xenotransplantation or co-culture with CAFs restores the individual transcriptomic status and instructs subtype-specific stromal gene expression. Furthermore, co-culture exposed CMS4-specific resistance to Gefitinib and SN-38 and revealed prognostic gene expression signatures. Chemogenomic library screening identified patient- and therapy-dependent mechanisms of stromal resistance including MET as common target. Our results demonstrate that CRC phenotypes are encrypted in the cancer epithelium in a plastic fashion that strongly depends on the context. Consequently, CAFs are essential for faithful representation of molecular subtypes and therapy responses ex vivo.

| EGAS00001007300 | EGA

074e2df0-10fb-4488-997a-f1a4c6dbceb2 - samples

| EGAD00001011173 | EGA

Proteome comparison of a new human cholangiocarcinoma 3D co-culture tumor model to 3D single cultures.

Project description:Cholangiocarcinomas (CCA) are characterized by their desmoplastic and hypervascularized tumor microenvironment (TME) which is mainly composed of tumor cells and cancer-associated fibroblasts (CAFs). CAFs play a pivotal role in tumor progression, angiogenesis, metastasis and the development of therapy resistance. To our knowledge, no continuous human in vivo-like co-culture model is available for research. Therefore, we aimed to establish a new model that mimics the desmoplastic environment typically seen in CCA. Proteomic data comparing the new CCA tumor cell line with our co-culture tumor model (CCTM) indicated a higher correlation of the CCTM with physiological CCA characteristics according to literature. A pro-angiogenic TME that is typically observed in CCA could also be simulated in the CCTM group. Further analysis of secreted proteins revealed CAFs to be the main source for these angiogenic factors. Our CCTM represents a new, reproducible and easy-to-handle 3D CCA model for preclinical studies focusing on CCA-stromal crosstalk, tumor angiogenesis and invasion, the immunosuppressive microenvironment and the involvement of CAFs in the way that drug resistance develops.

2023-05-10 | PXD037649 | Pride

The origin and contribution of the tumor stroma in colorectal carcinogenesis

Project description:Background and aims Cancer-associated fibroblasts (CAFs) play a critical role in colorectal cancer (CRC) progression. However, the precise cellular origins of the tumor stroma remain unknown, making it challenging to therapeutically target the tumor mesenchyme. Here, we aimed to identify key cellular contributors to and components of the CRC mesenchyme associated with poor prognosis. Methods We used a mouse model of inflammation-associated CRC in 5 different genetic fate-mapping transgenic mouse lines to characterize the origins of the CRC stroma. To identify a potential therapeutic target expressed by the CRC stroma, RNA-sequencing of fluorescence-activated cell sorting (FACS)-purified CRC stromal cells was performed. CRC patient RNA-sequencing data (n=621) and tissue microarray (n=101) were used to examine the prognostic significance of marker expression. Results We found that approximately half of the CRC CAFs marked by α-smooth muscle actin (αSMA) in a mouse model of CRC emerge through proliferation. Lineage tracing experiments revealed that intestinal leptin receptor (Lepr)-lineage stromal cells expanded and contributed to 75% of the αSMA+ proliferating CAFs. Notably, no αSMA+ CAFs arose from Krt19-lineage epithelial cells or bone marrow-derived cells. Moreover, RNA-sequencing of FACS-purified CRC mesenchymal cells identified MCAM as a CRC stroma-specific marker, which is expressed by Lepr-lineage cells. Analysis of human CRC samples showed that high MCAM expression driven, in part, by TGF-β was independently prognostic of poor overall survival. Conclusion Our data identify intestinal Lepr-lineage cells as a major source of the tumor stroma in CRC and suggest that targeting MCAM+ cells may serve as an attractive therapeutic approach to restrain CRC progression.

2022-11-01 | GSE162508 | GEO

The reprogramming of tumor stroma by HSF1 is a potent enabler of malignancy

Project description:Stromal cells within the tumor microenvironment are essential for tumor progression and metastasis. Yet surprisingly little is known about the factors that drive the transcriptional reprogramming of stromal cells within tumors. We report that the transcriptional regulator Heat-Shock Factor 1 (HSF1) is activated in cancer-associated fibroblasts (CAFs) and is a potent enabler of malignancy. In CAFs, HSF1 drives a transcriptional program that complements, yet is completely different from, the program it drives in adjacent cancer cells. This CAF program is uniquely structured to support the malignant potential of cancer cells in a non-cell-autonomous way and involves two central stromal signaling moleculesM-bM-^@M-^TTGFM-NM-2 and stromal-derived factor 1 (SDF1). As clinical confirmation, in early stage breast and lung cancer high stromal HSF1 activation is strongly associated with poor patient outcome. Thus, cancers co-opt the ancient, multifaceted survival functions of HSF1 to orchestrate malignant progression in unexpected ways that have far-reaching therapeutic implications. Gene expression data We used microarrays to examine the HSF1-dependent effect of co-culture on gene expression in cancer cells and fibroblasts. D2A1 mouse breast cancer cells were co-cultured with WT or Hsf1 null MEFs for 72h, afterwhich the two cell types were separated from each other by FACS and analyzed. Each cell type was also grown separately, as control.

2014-07-31 | E-GEOD-56252 | biostudies-arrayexpress

Gene expression profiles of interactions between colorectal cancer-associated fibroblasts and myeloid cells in 2D co-cultures and in novel next generation triple cultures containing colorectal cancer patient-derived organoids

Project description:In this study colorectal cancer (CRC) patient-derived cancer-associated fibroblasts (CAFs) and primary monocytes or macrophages were co-cultured in 2D set-up and single-cell transcriptomics was employed to analyze the phenotypic and functional changes of the myeloid cells and CAFs upon their interaction. The results showed that CAFs instruct monocytes to gain a tumor-associated macropages (TAM)-like cells phenotype. In the next step, novel next generation tumor organoid cultures of myelid cells, CAFs and patient-derived CRC organoids (PDOs) were utilized to mimic the tumor microenvironment and study the phenotypic changes of cells under chemotherapy and oncolytic virus treatments. The sequencing data revealed that both treatments triggered distinct phenotypic changes and identified immunomodulatory effects of chemotherapy in TAM-like cells. Oncolytic virus treatment led to strong upregulation of Type I and II interferon signaling, while both therapies activated multiple cell-cell communication pathways, highlighting key molecular interactions relevant to the tumor microenvironment. This co-culture model provided insights into TAM-like responses, aiding precision cancer treatment evaluations.

2024-10-13 | GSE279062 | GEO

Mimicking tumor cell heterogeneity of colorectal cancer in a patient-derived organoid-fibroblast model

Project description:Patient derived organoids (PDOs) have been established as a 3D culture model which closely recapitulates the in vivo tumor biology. However, one limitation of this culture model is the lack of tumor microenvironment which has a significant role in tumor progression and drug response. To address this, we established and molecularly characterized a novel 3D co-culture model of colorectal cancer (CRC) based on PDOs and patient matched fibroblasts. Both normal and cancer associated fibroblasts, NFs and CAFs respectively, were able to support organoid growth without addition of niche factors to the media. Additionally, co-cultures showed closer resemblance to primary patient material than organoid mono-cultures as evaluated by histology. Finally, RNA gene expression signatures of tumor cells and fibroblasts isolated from mono- or co-cultures demonstrated that co-cultures support greater cell type heterogeneity. In this proteomics dataset we compared pairs of NFs and CAFs derived from five patients. Collectively, we present a newly established human derived organoid-fibroblast model which, closely recapitulates in vivo tumor heterogeneity and involves the tumor microenvironment.

2023-03-14 | PXD032047 | Pride

Bulk RNA-seq analysis of 6 CAFs and 3 NAFs from human colorectal carcinoma

Project description:Cancer associated fibroblasts (CAFs, n=6) and corresponding Normal associated fibroblasts (NAFs, n=3) were isolated from human treatment-naive CRC patients, propagated under culture conditions and phenotypical differences were investigated using bulk RNA-sequencing.

2024-10-17 | E-MTAB-14208 | biostudies-arrayexpress

Enhanced antigen cross-presentation in human colorectal cancer-associated fibroblasts through upregulation of the lysosomal protease Cathepsin S

Project description:Cross-presentation of exogenous antigens in HLA-class I molecules by professional antigen presenting cells (APCs) is crucial for CD8+ T cell function. Recent murine studies show that several non-professional APCs, including cancer-associated fibroblasts (CAFs) also possess this capacity. It is currently unknown whether human CAFs are able to cross-present exogenous antigen, which molecular pathways are involved in this process and how this ultimately affects tumor-specific CD8+ T cell function. Here we show that human colorectal cancer (CRC)-derived CAFs display an enhanced capacity to cross-present neoantigen-derived synthetic long peptides (SLPs) when compared to normal colonic fibroblasts. Importantly, cross-presentation of antigens required the lysosomal protease Cathepsin S. Cathepsin S expression by CAFs was detected in situ in human CRC tissue, was upregulated in ex vivo cultured CRC-derived CAFs and showed increased expression in normal fibroblasts after exposure to CRC-conditioned medium. Cognate interaction between CD8+ T cells and cross-presenting CAFs suppressed T cell function, reflected by decreased cytotoxicity, reduced activation (CD25, CD137) and increased exhaustion (TIM3) marker expression. Our data indicate that CAFs may directly suppress tumor-specific T cell function in an antigen-dependent fashion in human CRC.

2022-03-03 | PXD029507 | Pride

Targeting stromal cell sialylation reverses T cell mediated immunosuppression in the tumor microenvironment

Project description:Immunosuppressive tumor microenvironments (TME) reduce the effectiveness of immune responses in cancer. Mesenchymal stromal cells (MSC), precursors to cancer-associated fibroblasts (CAFs), dictate tumor progression by enhancing immune cell suppression in colorectal cancer (CRC). Hyper-sialylation of glycans promotes immune evasion in cancer through binding of sialic acids to their receptors, Siglecs, expressed on immune cells that results in inhibition of effector functions. The role of sialylation in dictating MSC/CAF immunosuppression in the TME is unknown. In this study, we show that tumor-conditioned stromal cells have increased sialyltransferase expression, α2,3/6-linked sialic acid and Siglec ligands. Tumor-conditioned stromal cells and CAFs induce exhausted immunomodulatory PD-1, Siglec-7 and Siglec-9-expressing T cell phenotypes. In vivo, targeting stromal cell sialylation reverses stromal cell-mediated immunosuppression, as evidenced by infiltration of CD25 and granzyme B-expressing T cells in the tumor and draining lymph node. Targeting stromal cell sialylation may overcome immunosuppression in the CRC TME.

2023-05-22 | GSE229054 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data