Targeting biliary cancer desmoplasia in culture
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ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE70587 | GEO | 2016/05/31
SECONDARY ACCESSION(S): PRJNA289112
REPOSITORIES: GEO
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Project description:To more closely reproduce key cellular and stromal features of the desmoplastic reaction of cholangiocarcinoma in vitro, we developed a novel 3-dimensional culture modeling of cancer and stromal cells as a strategy for targeted therapies Cellular, molecular, and functional characterization of different cancer-associated fibroblastic (CAF) and cholangiocarcinoma cell strains isolated from orthotopic tumors arising from bile duct inoculation of spontaneously-transformed rat cholangiocytes (BDEsp cells) in Fischer 344 young adult male rats.
2016-05-31 | E-GEOD-70587 | biostudies-arrayexpress
Project description:Cholangiocarcinoma (CCA) is a hepatobiliary malignancy with dismal prognosis. Currently available models fail to recapitulate the full complexity of CCA, particularly the desmoplastic environment and the interplay between cancer cells and the extracellular matrix (ECM). We aimed to study the role of epithelial tumor cells in ECM deposition and desmoplasia by designing a model encompassing primary epithelial CCA organoids (CCAOs) and native liver and tumor scaffolds obtained by decellularization Background & Aims: Cholangiocarcinoma (CCA) is a hepatobiliary malignancy with dismal prognosis. Currently available models fail to recapitulate the full complexity of CCA, particularly the desmoplastic environment and the interplay between cancer cells and the extracellular matrix (ECM). We aimed to study the role of epithelial tumor cells in ECM deposition and desmoplasia by designing a model encompassing primary epithelial CCA organoids (CCAOs) and native liver and tumor scaffolds obtained by decellularization. Results: Decellularization resulted in effective removal of cells while preserving ECM structure and retaining important characteristics of the tissue origin. When culturing CCAOs in CCA-M, compared to TFL-M and BME, the genome-wide gene expression profile much more resembled the transcriptome of primary CCA tumor tissue in vivo, with an accompanying increase in chemoresistance. CCAOs in decellularized matrix, both CCA-M and TFL-M, exhibited the formation of complex morphological structures, and revealed environment-dependent proliferation and migration dynamics, driven by the occurrence of epithelial-mesenchymal transition (EMT). CCA-M induced specific extracellular matrix protein production in CCAOs, such as fibronectin 1 (FN1), which is related to desmoplasia and patient survival. In TFL-M, lacking the desmoplastic environment, CCAOs were able to initiate a desmoplastic reaction directly through increased production of multiple collagen types. Conclusions: This improved model of cholangiocarcinoma, combining organoids and native extracellular matrix, recapitulates key components of CCA tumor biology, including transcriptome profiles, migration patterns, EMT, and ECM protein production. The increased production of extracellular matrix proteins suggests that epithelial tumor cells can contribute to their own desmoplastic environment.
2022-12-31 | GSE188527 | GEO
Project description:The increased α-smooth muscle-actin positive cancer-associated fibroblastic cells (CAF) in the desmoplastic stroma may relate to a more aggressive cancer and worse survival outcomes for intrahepatic cholangiocarcinoma (ICC) patients We developed a novel 3-D organotypic culture model by co-culturing α-SMA positive CAF and cholangiocarcinoma cells in a collagen matrix.
2012-06-23 | GSE38889 | GEO
Project description:The increased M-NM-1-smooth muscle-actin positive cancer-associated fibroblastic cells (CAF) in the desmoplastic stroma may relate to a more aggressive cancer and worse survival outcomes for intrahepatic cholangiocarcinoma (ICC) patients We developed a novel 3-D organotypic culture model by co-culturing M-NM-1-SMA positive CAF and cholangiocarcinoma cells in a collagen matrix. Cholangiocarcinoma cell lines were established by isolating M-NM-1-SMA positive cancer-associated fibroblastic cells (CAF) (BDEsp-TDFE4) and cholangiocarcinoma cells (BDEsp-TDEH10) from tumors arising from bile duct inoculation of spontaneously-transformed low grade malignant rat BDE1 cholangiocytes (BDEsp cells). These tumor-derived cells lines were then grown in a rat tail type I collagen gel matrix, alone or in co-culture, and their gene expression profile were compared.
2012-06-22 | E-GEOD-38889 | biostudies-arrayexpress
Project description:Bioengineered tumoral microtissues recapitulate desmoplastic reaction of pancreatic cancer
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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
Project description:Here we analyzed mouse and human samples to characterize origin, subtypes, functions and cell-cell interactions of cancer-associated fibroblasts in cholangiocarcinoma, a highly desmoplastic tumor of the liver. Hepatic stellate cell-derived cancer-associated fibroblasts were isolated from two different models of murine intrahepatic cholangiocarcinoma, induced by overexpression of YAP+AKT or KRASG12D in combination with sg-p19, and compared by bulk RNA-sequencing to hepatic stellate cells from two models of liver fibrosis, induced by bile duct ligation or DDC diet. CAF-enriched fractions of from YAP+AKT or KRAS/sg-p19-induced intrahepatic cholangiocarcinoma, were analyzed by single-cell RNA sequencing. A cell suspension from human cholangiocarcinoma, containing all cell populations, was analyzed by single cell RNA-sequencing.
2021-04-28 | GSE154170 | GEO
Project description:Endometriotic cyst stromal cells (ECSCs) were isolated from ovarian endometriotic cyst and cultured for 48 hours in the floating three-dimensional collagen gel culture or in the conventional two-dimensional culture. Total mRNAs were extracted and subjected to gene expression microarray.
2020-07-31 | GSE136412 | GEO
Project description:APOBEC3s-related somatic mutations are the predominant burden in biliary tract cancers (BTCs). Here, we reveal the effects and mechanisms of APOBEC3A/3B functional polymorphisms on cholangiocarcinoma and gallbladder cancer (GBC). rs2267401-G at the APOBEC3B promoter decreases cholangiocarcinoma risk but increased GBC risk. rs2267401-G confers a decreased APOBEC3B promoter activity in cholangiocarcinoma cells but an increased activity in GBC cells. rs12157810-C at the APOBEC3A promoter decreases the risk of BTCs. rs12157810-C up-regulated the promoter activity in both cells. APOBEC3A overexpression attenuates cancer evolution via causing apoptosis, in contrast to APOBEC3B. Inflammatory factors promote cancer evolution via interacting with transcriptional repressors regulating the APOBEC3A/3B promoters. ATAC-seq was used to identify the difference between transcriptional networks of cholangiocarcinoma and GBC.
2022-01-07 | GSE166372 | GEO
Project description:The desmoplastic reaction observed in many cancers is a hallmark of disease progression and prognosis, particularly in breast and pancreatic cancer. Stromal-derived extracellular matrix (ECM) is significantly altered in desmoplasia, and as such plays a critical role in driving cancer progression. Using fibroblast-derived matrices (FDMs), we show that cancer cells have increased growth on cancer-associated FDMs, comparing to FDMs derived from non-malignant tissue (normal) fibroblasts. We assess the changes in ECM characteristics from normal to cancer-associated stroma at the primary tumor site. Compositional, structural, and mechanical analyses reveal significant differences, with an increase in abundance of core ECM proteins, coupled with an increase in stiffness and density in cancer-associated FDMs. From compositional changes of FDM we derived a 36-ECM proteins’ signature, which we show largely matching the changes in pancreatic ductal adenocarcinoma (PDAC) tumor and metastases progression, as well as at the transcriptomic level in multiple cancer types in patients, predictive of their survival. Together, our results show relevance of FDMs for cancer modelling and identification of desmoplastic ECM components for further mechanistic studies.
2023-07-17 | PXD042342 | Pride