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A tissue-engineered mimic of the ovarian cancer microenvironment of increases cell proliferation and tumor growth.

ABSTRACT: Using tissue engineering technologies, we aimed to engineer the ovarian tumor microenvironment to study disease progression by combining biomimetic hydrogels with melt electrospun written scaffolds. 3D co-cultures were constructed by assembling ovarian cancer cell-laden hydrogels with mesothelial cell-layered scaffolds. 3D constructs were characterised by proliferation and transcriptomic analyses and applied to an intraperitoneal xenograft model. Increased cancer cell proliferation upon 3D co-cultures was validated using patient-derived cells and linked to greater tumor burden in vivo. Genome-wide microarray analysis identified IGFBP7, PTGS2, VEGFC and FGF2 as being upregulated in 3D co-cultures compared to 3D mono-cultures. Protein expression of these differentially regulated factors was confirmed by immunohistochemistry in xenograft and patient-derived tumor tissues and correlated with overall and progression-free survival. This pre-clinical cancer model harbors the complexity of the disease seen in patients and advances our understanding of the underlying cell biology and the contribution of the tumor microenvironment to cancer growth.

ORGANISM(S): Homo sapiens

PROVIDER: GSE109577 | GEO | 2018/01/25

REPOSITORIES: GEO

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A preclinical platform for assessing long-term drug efficacy exploiting mechanically tunable scaffolds colonized by a three-dimensional tumor microenvironment

Project description:Background: Long-term drug evaluation heavily relies upon rodent models. Drug discovery methods to reduce animal models in oncology may include three-dimensional (3D) cellular systems that take into account tumor microenvironment (TME) cell types and biomechanical properties. Methods: In this study we reconstructed a 3D tumor using an elastic polymer (acrylate-endcapped urethane-based poly(ethylene glycol) (AUPPEG)) with clinical relevant stiffness. Single cell suspensions from low-grade serous ovarian cancer (LGSOC) patient-derived early passage cultures of cancer cells and cancer-associated fibroblasts (CAF) embedded in a collagen gel were introduced to the AUPPEG scaffold. After self-organization in to a 3D tumor, this model was evaluated by a long-term (>40 days) exposure to a drug combination of MEK and HSP90 inhibitors. The drug-response results from this long-term in vitro model are compared with drug responses in an orthotopic LGSOC xenograft mouse model. Results: The in vitro 3D scaffold LGSOC model mimics the growth ratio and spatial organization of the LGSOC. The AUPPEG scaffold approach allows to test new targeted treatments and monitor long-term drug responses. The results correlate with those of the orthotopic LGSOC xenograft mouse model. Conclusions: The mechanically-tunable scaffolds colonized by a three-dimensional LGSOC allow long-term drug evaluation and can be considered as a valid alternative to reduce, replace and refine animal models in drug discovery

2024-01-26 | PXD039590 | Pride

Fibrin Hydrogels Induce Mixed Dorsal/Ventral Spinal Neuron Identities During Differentiation of Human Induced Pluripotent Stem Cells

Project description:We hypothesized that generating spinal motor neurons (sMNs) from human induced pluripotent stem cell (hiPSC)-derived neural aggregates (NAs) using a chemically-defined differentiation protocol would be more effective inside of 3D fibrin hydrogels compared to 2D poly-L-ornithine(PLO)/laminin-coated tissue culture plastic surfaces. We performed targeted RNA-Seq using next generation sequencing to determine the substrate-specific differences in gene expression that regulate cell phenotype. Cells cultured on both substrates expressed sMN genes CHAT and MNX1, though persistent WNT signaling contributed to a higher expression of genes associated with interneurons in NAs cultured in 3D fibrin scaffolds. Cells in fibrin also expressed lower levels of astrocyte progenitor genes and higher levels of the neuronal-specific gene TUBB3, suggesting a purer population of neurons compared to 2D cultures. STATEMENT OF SIGNIFICANCE: Fibrin scaffolds can support the neuronal differentiation of pluripotent stem cells. This study provides insight into how fibrin hydrogels affect neuronal induction by analyzing of the signaling pathways activated during the differentiation process. These insights can then be used to tailor the properties of these hydrogels to optimize the generation of sMNs for regenerative medicine applications.

2017-01-17 | GSE79442 | GEO

Gene expression profiles of triple-negative breast cancer cells under the condition of 3D proliferation

Project description:Triple-negative breast cancer (TNBC) is defined by the absence of estrogen and progesterone receptors and human epidermal growth factor receptor 2, and is the most lethal and aggressive subtype of breast cancer. However, the genes which relate to promote tumor aggressiveness in TNBC remain unclear. In order to investigate specific genes and pathways involved in TNBC tumorigenesis, we compared genes differentially expressed between 3D cultures (3DC) or tumor xenograft models and control two-dimensional cultures (2DC). Total RNA was prepared from the TNBC cells under the condition of 2DC, 3DC and tumor xenograft models, and applied to Affymetrix Human Genome U133 Plus 2.0 Array.

2012-04-30 | E-GEOD-36953 | biostudies-arrayexpress

Patient-derived scaffolds uncover breast cancer promoting properties of the microenvironment

Project description:Tumor cells interact with the microenvironment that specifically supports and promotes tumor development. Key components in the tumor environment have been linked to various aggressive cancer features and can further influence the presence of subpopulations of cancer cells with specific functions, including cancer stem cells and migratory cells. To model and further understand the influence of specific microenvironments we have developed an experimental platform using cell-free patient-derived scaffolds (PDSs) from primary breast cancers infiltrated with standardized breast cancer cell lines. This PDS culture system induced a series of orchestrated changes in differentiation, epithelial-mesenchymal transition, stemness and proliferation of the cancer cell population, where an increased cancer stem cell pool was confirmed using functional assays. Furthermore, global gene expression profiling showed that PDS cultures were similar to xenograft cultures. Mass spectrometry analyses of cell-free PDSs identified subgroups based on their protein composition that were linked to clinical properties, including tumor grade. Finally, we observed that an induction of epithelial-mesenchymal transition-related genes in cancer cells growing on the PDSs were significantly associated with clinical disease recurrences in breast cancer patients. Patient-derived scaffolds thus mimics in vivo-like growth conditions and uncovers unique information about the malignancy-inducing properties of tumor microenvironment.

2020-06-25 | PXD018367 | Pride

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

Transcription profiling of human dermal fibroblasts after 3 hours of cyclic mechanical loading compared with ni loading - collagen 1 hydrogel dynamic loading tests

Project description:Cell viability and global gene expression was anayzed from collagen 1 hydrogel scaffolds following 3 hours of cyclic mechanical loading and compared with non-loaded scaffolds. Experiment Overall Design: 6 samples are analyzed (2 sets in triplicate). The first set is the Loaded condition in which Collagen 1 hydrogels seeded with Human dermal fibroblasts underwent cyclic loading of 0.1Hz for 180 minutes at 37 degrees Celsius. The second set is the control Unloaded condition in which the Collagen 1 hydrogels seeded with Human dermal fibroblasts are incubated at 37 degrees Celsius with no loading.

2008-06-11 | E-GEOD-10125 | biostudies-arrayexpress

Gene expression profiles of triple-negative breast cancer cells under the condition of 3D proliferation

2012-05-01 | GSE36953 | GEO

Patient-derived scaffolds uncover breast cancer promoting properties of the microenvironment

Project description:Tumor cells interact with the microenvironment that specifically supports and promotes tumor development. Key components in the tumor environment have been linked to various aggressive cancer features and can further influence the presence of subpopulations of cancer cells with specific functions, including cancer stem cells and migratory cells. To model and further understand the influence of specific microenvironments we have developed an experimental platform using cell-free patient-derived scaffolds (PDSs) from primary breast cancers infiltrated with standardized breast cancer cell lines. This PDS culture system induced a series of orchestrated changes in differentiation, epithelial-mesenchymal transition, stemness and proliferation of the cancer cell population, where an increased cancer stem cell pool was confirmed using functional assays. Furthermore, global gene expression profiling showed that PDS cultures were similar to xenograft cultures. Mass spectrometry analyses of cell-free PDSs identified subgroups based on their protein composition that were linked to clinical properties, including tumor grade. Finally, we observed that an induction of epithelial-mesenchymal transitionrelated genes in cancer cells growing on the PDSs were significantly associated with clinical disease recurrences in breast cancer patients. Patient-derived scaffolds thus mimics in vivo-like growth conditions and uncovers unique information about the malignancy-inducing properties of tumor microenvironment.

2020-04-11 | GSE148483 | GEO

Expression profiles of lncRNAs in 3D cultures.

Project description:Breast cancer cells reprogram the oncogenic lncRNAs/mRNAs co-expression networks in three- dimensional microenvironment To have a more functional approach, organotypic 3D cell cultures that more accurately mimic the characteristics of solid tumors in vivo and the tumor microenvironment are required. In this study, DNA microarrays were employed to deline the changes in lncRNAs expression patterns of breast cancer cells, cultured in 3D and 2D conditions from BT-474 cell line. Furthermore, potential lncRNAs/mRNAs pairs co-expressed in 3D cultures exhibit a high degree of similarity with those found in luminal B breast cancer patients suggesting that they could be adequate pre-clinical tools to identify, not only biomarkers related to endocrine therapy response and PCR, but to understand the biological behavior of cancer cells in 3D microenvironments, which point towards an important contribution of the roles of lncRNAs in organotypic 3D cultures.

2022-06-24 | GSE206836 | GEO

Xenografted Tumor decellularization provides cell-specific in vitro 3D environment

Project description:In vitro cell culture studies are common in cancer research field, and reliable biomimetic 3D models are needed to ensure physiological relevance. In this manuscript, we hypothesized that decellularized xenograft tumors can serve as an optimal 3D substrate to generate a top-down approach for in vitro tumor modeling. Methods: Multiple tumor cell lines were xenografted and the formed solid tumors were recovered for their decellularization by several techniques and further characterization by histology and proteomics techniques. Selected decellularized tumor xenograft samples were seeded with human triple negative breast cancer (TNBC)c ells and cell behavior was compared among them and with other control 2D and 3D cell culture methods. Results: A soft treatment using Freeze-EDTA-DNAse allows proper decellularization of xenografted tumor samples. Interestingly, proteomic data show that samples decellularized from TMBC xenograft models had different extracellular matrix (ECM) composition compared to the rest of xenograft tumors tested. The in vitro re-cellularization of decellularized ECM (dECM) yields tumor-type specific cell-behavior in TNBC context. Conclusions: Data indicate that dECM derived from xenograft tumors is a feasible substrate for re-seeding purposes, thereby promoting tumor-type specific cell behavior. These data serve as a proof-of-concept for further potential generation of patient-specific in vitro research models.

2022-09-12 | PXD034597 | Pride

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