A three-dimensional ex vivo model recapitulates in vivo features and unravels increased drug resistance in childhood acute lymphoblastic leukemia
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE282806 | GEO | 2025/09/16
REPOSITORIES: GEO
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Project description:A three-dimensional ex vivo model recapitulates in vivo features and unravels increased drug resistance in childhood acute lymphoblastic leukemia
| PRJNA1190451 | ENA
Project description:BackgroundIn vitro models of prostate cancer (PCa) are not always reliable to evaluate anticancer treatment efficacy. This limitation may be overcome by using viable tumor slice material. Here we report on the establishment of an optimized ex vivo method to culture tissue slices from patient-derived xenografts (PDX) of prostate cancer (PCa), to assess responses to PCa treatments.MethodsThree PDX models were used that are characterized by different androgen receptor (AR) expression and different homology directed DNA repair capacities, due to a breast cancer associated two (BRCA2) wild-type or mutated status. Tumors were removed from mice, sliced using a vibratome and cultured for a maximum of 6 days. To test the sensitivity to androgen antagonist, tumor slices from the AR-expressing and AR-negative PDX tumors were treated with the anti-androgen enzalutamide. For sensitivity to DNA repair intervention, tumors slices from BRCA2 wild-type and mutated PDXs were treated with the poly (ADP-ribose) polymerase-1 inhibitor olaparib. Treatment response in these tumor slices was determined by measuring slice morphology, cell proliferation, apoptosis, AR expression level, and secretion of prostate specific antigen (PSA).ResultsWe compared various culture conditions (support materials, growth media, and use of a 3D smooth rocking platform) to define the optimal condition to maintain tissue viability and proliferative capacity up to least 6 days. Under optimized conditions, enzalutamide treatment significantly decreased proliferation, increased apoptosis, and reduced AR-expression and PSA secretion of AR-expressing tumor slices compared to AR-negative slices, that did not respond to the intervention. Olaparib treatment significantly increased cell death in BRCA2 mutated tumors slices as compared to slices from BRCA2 wild type tumors.ConclusionsEx vivo treatment of PCa PDX tumor slices with enzalutamide and olaparib recapitulates responses previously observed in vivo. The faithful retention of tissue structure and function in this ex vivo model offers an ideal opportunity for treatment efficacy screening, thereby reducing costs and numbers of experimental animals.
| S-EPMC6587720 | biostudies-literature
Project description:Prostate cancer (PCa) is the second leading cause of cancer deaths among American men. Unfortunately, there is no cure once the tumor is established within the bone niche. Although osteocytes are master regulators of bone homeostasis and remodeling, their role in supporting PCa metastases remains poorly defined. This is largely due to a lack of suitable ex vivo models capable of recapitulating the physiological behavior of primary osteocytes. To address this need, we integrated an engineered bone tissue model formed by 3D-networked primary human osteocytes, with conditionally reprogrammed (CR) primary human PCa cells. CR PCa cells induced a significant increase in the expression of fibroblast growth factor 23 (FGF23) by osteocytes. The expression of the Wnt inhibitors sclerostin and dickkopf-1 (Dkk-1), exhibited contrasting trends, where sclerostin decreased while Dkk-1 increased. Furthermore, alkaline phosphatase (ALP) was induced with a concomitant increase in mineralization, consistent with the predominantly osteoblastic PCa-bone metastasis niche seen in patients. Lastly, we confirmed that traditional 2D culture failed to reproduce these key responses, making the use of our ex vivo engineered human 3D bone tissue an ideal platform for modeling PCa-bone interactions.
| S-EPMC6299475 | biostudies-literature
Project description:Glucocorticoids are critical components of combination chemotherapy regimens in pediatric acute lymphoblastic leukemia (ALL). The pro-apoptotic BIM protein is an important mediator of glucocorticoid-induced apoptosis in normal and malignant lymphocytes, while the anti-apoptotic BCL2 confers resistance. The signaling pathways regulating BIM and BCL2 expression in glucocorticoid-treated lymphoid cells remain unclear. In this study, pediatric ALL patient-derived xenografts (PDXs) inherently sensitive or resistant to glucocorticoids were exposed to dexamethasone in vivo. In order to understand the basis for differential in vivo glucocorticoid sensitivity of PDXs, microarray analysis of gene expression was carried out on 5 each of dexamethasone-sensitive and resistant PDXs . This provided a global understanding of dexamethasone-induced signaling cascades in ALL cells in vivo, and especialy identified the genes that are involved in transducing the apoptotic signal, upstream of BIM/BCL2 dynamic interactions.
2014-05-20 | GSE57795 | GEO
Project description:Glucocorticoids are critical components of combination chemotherapy regimens in pediatric acute lymphoblastic leukemia (ALL). The pro-apoptotic BIM protein is an important mediator of glucocorticoid-induced apoptosis in normal and malignant lymphocytes, while the anti-apoptotic BCL2 confers resistance. The signaling pathways regulating BIM and BCL2 expression in glucocorticoid-treated lymphoid cells remain unclear. In this study, pediatric ALL patient-derived xenografts (PDXs) inherently sensitive or resistant to glucocorticoids were exposed to dexamethasone in vivo. In order to understand the basis for differential in vivo glucocorticoid sensitivity of PDXs, microarray analysis of gene expression was carried out on 5 each of dexamethasone-sensitive and resistant PDXs . This provided a global understanding of dexamethasone-induced signaling cascades in ALL cells in vivo, and especialy identified the genes that are involved in transducing the apoptotic signal, upstream of BIM/BCL2 dynamic interactions. ALL xenograft cells were inoculated by tail-vein injection into NOD/SCID mice, and engraftment was monitored weekly. When >70% %huCD45+ engraftment in the peripheral blood was apparent, which occurred 8-10 weeks post-transplantation, mice were treated with either dexamethasone (15 mg/kg) or vehicle control by intra-peritoneal (IP) injection, and culled at 8 hours following the treatment. Cell suspensions of spleens were prepared and mononuclear cells enriched to >97% human by density gradient centrifugation. RNA was extracted using the RNeasy Mini Kit (QIAGEN, Valencia, CA, USA), and RNA samples with integrity number (RIN) > 8.0 were amplified and hybridized onto Illumina HumanWG-6 v3 Expression BeadChips (6 samples/chip). All chips (with associated reagents) were purchased from Illumina, and scanned on the Illumina BeadArray Reader according to the manufacturer’s instructions. Microarray data were analyzed using the online modules in GenePattern. 10 xenografts were derived from patients of 5 dexamethasone-good responder and 5 dexamethasone-poor responder. Each xenograft was innoculated into 5-6 mice, and treated with dexamethasone (15 mg/kg) or vehicle control. In total spleen-harvest xenograft samples from 58 mice were analyzed using microarray.
2014-05-20 | E-GEOD-57795 | biostudies-arrayexpress
Project description:BackgroundWe have developed a four-dimensional (4D) lung cancer model that forms perfusable tumor nodules. We determined if the model could be modified to mimic metastasis.MethodsWe modified the 4D lung cancer model by seeding H1299, A549, or H460 cells through the trachea only to the left lobes of the acellular lung matrix. The model was modified so that the tumor cells can reach the right lobes of the acellular lung matrix only through the pulmonary artery as circulating tumor cells (CTC). We determined the gene expressions of the primary tumor, CTCs, and metastatic lesions using the Human OneArray chip.ResultsAll cell lines formed a primary tumor in the left lobe of the ex vivo 4D lung cancer model. The CTCs were identified in the media and increased over time. All cell lines formed metastatic lesions with H460 forming significantly more metastatic lesions than H1299 and A549 cells. The CTC gene signature predicted poor survival in lung cancer patients. Unique genes were significantly expressed in CTC compared with the primary tumor and metastatic lesion.ConclusionsThe 4D lung cancer model can isolate tumor cells in 3 phases of tumor progression. This 4D lung cancer model may mimic the biology of lung cancer metastasis and may be used to determine its mechanism and potential therapy in the future.
| S-EPMC4387006 | biostudies-literature
Project description:The ex vivo modelling of pancreatic ductal adenocarcinoma (PDAC) using patient-derived cells is a promising tool to predict treatment responses. Matrigel-based organoid and organotypic approaches are limited by their undefined molecular composition, hindering the recapitulation of the tumour’s characteristic desmoplasia, which is known to promote drug resistance. To overcome these limitations, we used self-assembling peptide amphiphiles (PAs) gelled in a minimal extracellular matrix to model the pancreatic tumour microenvironment and to establish 3D multicellular cultures of patient-derived PDAC cells, pancreatic stellate cells and macrophages. Matrisome analysis of 3D cultures demonstrated consistent ECM protein deposition, which was highly reminiscent of the corresponding primary PDAC tissues. The proteomic data obtained was also compared to the corresponding patient-derived xenografts (PDX) in nude mice and Matrigel-based cultures. Characterisation of the chemosensitivity of the cultures revealed realistic treatment responses by PDAC cells in PA hydrogels based on the responses of their corresponding PDX tumours. Histological, transcriptional and functional techniques confirmed these similarities, which were not observed in Matrigel-based cultures. These findings demonstrate the biomimetic nature of PA hydrogels, which enable cultured cells to recreate the PDAC matrisome ex vivo and to respond to chemotherapeutic agents in a predictive manner.
2021-07-06 | PXD013254 | Pride
Project description:The thrombocytopenia of Wiskott-Aldrich syndrome (WAS) is thought to be due to both reduced platelet production and accelerated platelet consumption. We have previously demonstrated that platelets from WASP-deficient mice are consumed more rapidly in vivo than are WT platelets, and that opsonization accelerates their uptake by bone marrow- derived macrophages more than it does that of WT platelets. Here we asked whether platelets from WAS patients show similar features. We show that ex vivo phagocytosis by activated THP-1 cells of DIO-labeled platelets from a series of WAS or XLT patients is increased in comparison to that of normal control platelets. Using a numerical analysis method, we distinguish this effect from a concurrent effect on the amount of detectable fluorescent signal transferred to the macrophage per phagocytosed platelet. We show that the latter quantity is reduced by platelet WASP deficiency, as might be expected if the fluorescence transferred from these smaller platelets is more rapidly quenched. We are unable to detect a differential effect of opsonization with anti-CD61 antibody on the uptake of WASP(-) vs. WT platelets. However, the high probability of phagocytosis per adsorbed WASP(-) platelet could limit the sensitivity of the assay in this case. We also see no effect of sera from WAS patients on the uptake of normal control platelets, suggesting that in vivo opsonization is not the cause of increased uptake of WASP(-) platelets. Finally, we show little, if any, increase in the reticulated platelet fraction in WAS patients, suggesting that impaired production of reticulated platelets contributes to the thrombocytopenia. Our findings suggest that rapid in vivo platelet consumption contributes significantly to the thrombocytopenia of WAS. They also demonstrate the feasibility of routinely performing functional assays of phagocytosis of small numbers of platelets obtained at remote locations, a method which should be applicable to the study of other types of thrombocytopenia such as ITP.
| S-EPMC3529772 | biostudies-literature
Project description:Objectives: This study assessed associations of the miR196a2 (rs11614913) T>C polymorphism withsusceptibility
| S-EPMC5494224 | biostudies-literature
Project description:In this study, pediatric ALL patient-derived xenografts (PDXs) inherently resistant to glucocorticoids were cultured in vitro. The study aims to determine discrepancy in gene expressions between different xeno strains. The same xenograft was innoculated into 3 mice. Spleen-harvest xenograft samples were analyzed using microarray.
2015-10-24 | E-GEOD-74299 | biostudies-arrayexpress