Biophysically patterned glioblastoma model via rapid 3D bioprinting for investigation of tumorigenesis and angiogenesis
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE158097 | GEO | 2021/04/21
REPOSITORIES: GEO
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2019-05-31 | GSE131968 | GEO
Project description:Extracellular biophysical cues such as matrix stiffness are key stimuli tuning cell fate and affecting tumor progression in vivo. However, it remains unclear how spheroids in a 3D microenvironment perceive matrix mechanical stiffness stimuli and translate them into intracellular signals driving cancer. Mechanosensitive Piezo1 and TRPV4 ion channels, upregulated in many malignancies, are major transducers of such physical stimuli into biochemical responses. Most mechanotransduction studies probing the reception of changing stiffness cues by cells are, however, still limited to 2D culture systems or cell-extracellular matrix models which lack the major cell-cell interactions prevalent in 3D cancer tumors. Here, we engineered a 3D spheroid culture environment with varying mechanobiological properties to study the effect of static matrix stiffness stimuli on mechanosensitive and malignant phenotypes in oral squamous cell carcinoma spheroids. We find that spheroid growth is enhanced when cultured in stiff extracellular matrix. Using flow cytometry, we show that the expression of mechanoreceptor Piezo1 and stemness marker CD44 is upregulated in stiff matrix. We also report the upregulation of a selection of genes with associations to mechanoreception, ion channel transport, extracellular matrix organization, and tumorigenic phenotypes in stiff matrix spheroids. Together, our results indicate that cancer cells in 3D spheroids utilize mechanosensitive ion channels Piezo1 and TRPV4 to sense changes in static extracellular matrix stiffness and that stiffness drives pro-tumorigenic phenotypes in oral squamous cell carcinoma.
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Project description:Podocytes are terminally differentiated cells at the kidney filtration barrier and exposed to considerable mechanical strain. Podocyte injury causes morphological changes as a result of cytoskeletal reorganizations and failure of the filtration barrier. The transcriptional co-activators YAP/TAZ are tightly controlled through hippo signaling and responsive to mechanical cues. Here, we show that YAP is upregulated upon podocyte injury to activate YAP-dependent target genes. This activation preceded the development of proteinuria. In contrast, similar perturbations of cells in culture did not reveal increased YAP activity but showed a downregulation of YAP/TAZ activity when cells were grown on stiff surface. However, culture of cells on soft matrix or inhibition of stress fiber formation allowed recapitulation of the damage-induced YAP upregulation indicating a mechanotransduction-dependent mechanism of YAP over-activity. Interestingly, increased expression of YAP targets was confirmed in renal biopsies from patients with glomerular disease. Consistently, pharmacological inhibition of YAP/TEAD activity ameliorated glomerular disease in vivo. These data suggest that perturbation of the mechanosensitive hippo signaling pathway may be a therapeutic principle in podocyte disease.
2017-04-19 | PXD003872 | Pride
Project description:Podocytes are terminally differentiated cells at the kidney filtration barrier and exposed to considerable mechanical strain. Podocyte injury causes morphological changes as a result of cytoskeletal reorganizations and failure of the filtration barrier. The transcriptional co-activators YAP/TAZ are tightly controlled through hippo signaling and responsive to mechanical cues. Here, we show that YAP is upregulated upon podocyte injury to activate YAP-dependent target genes. This activation preceded the development of proteinuria. In contrast, similar perturbations of cells in culture did not reveal increased YAP activity but showed a downregulation of YAP/TAZ activity when cells were grown on stiff surface. However, culture of cells on soft matrix or inhibition of stress fiber formation allowed recapitulation of the damage-induced YAP upregulation indicating a mechanotransduction-dependent mechanism of YAP hyper-activity. Interestingly, increased expression of YAP targets was confirmed in renal biopsies from patients with glomerular disease. Consistently, pharmacological inhibition of YAP/TEAD activity ameliorated glomerular disease in vivo. These data suggest that perturbation of the mechanosensitive hippo signaling pathway may be a therapeutic principle in podocyte disease.
2017-05-02 | PXD003864 | Pride
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2019-07-06 | GSE133886 | GEO
Project description:In this study, we isolated GBM TSs and extracellular matrices (ECM) from tissues obtained from newly diagnosed IDH1 wild-type GBM patients, and cultured GBM TSs on five different culture platforms: (1) ordinary TS culture liquid media (LM), (2) collagen-based three-dimensional (3D) matrix, (3) patient normal ECM-based 3D matrix, (4) patient tumor ECM-based 3D matrix, and (5) mouse brain. To evaluate each culture platform, we obtained transcriptome data of all cultured GBM TSs using microarrays. The LM platform exhibited the most similar transcriptional program to paired tissues based on the four aspects, including GBM genes, stemness- and invasiveness-related genes, transcription factor activity, and canonical signaling pathways. GBM TSs can be cultured via an easy-to-handle, cost-efficient, and time-saving LM platform while preserving the transcriptional program of the originating tissues without supplementing artificially manipulated or patient-derived ECM or embedding into the mouse brain to imitate the tumor microenvironment of brain. In addition to applications in basic cancer research, GBM TSs cultured in LM may also serve as patient avatars in drug screening and pre-clinical evaluation of targeted therapy, and may function as a standardized and clinically relevant model for precision medicine owing to its scalability and reproducibility.
2023-12-06 | MSV000093581 | MassIVE
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