The substrate stiffness regulates the recurrent GBM cell morphology and aggressiveness
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ABSTRACT:
PROVIDER: PRJEB49973 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR7959161_1.fastq.gz | Fastqsanger.gz | |||
| ERR7959161_2.fastq.gz | Fastqsanger.gz | |||
| ERR7959162_1.fastq.gz | Fastqsanger.gz | |||
| ERR7959162_2.fastq.gz | Fastqsanger.gz | |||
| ERR7959163_1.fastq.gz | Fastqsanger.gz |
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Project description:Treating recurrent GBM is a clinical challenge due to its highly resistant and aggressive nature. In order to develop new therapeutic targets for recurrent GBM a better understanding of its molecular landscape is necessary. Here we used a cellular model, developed in our lab which generates paired primary and recurrent samples from GBM cell lines and primary patient samples hence allowing us to compare the molecular differences between the two populations. Total RNA seq analysis of parent and recurrent population of two cell lines and one patient sample revealed a significant upregulation of Extracellular matrix interaction in recurrent population. Since matrix stiffness plays a pivotal role in cell-ECM interaction and downstream signaling, we developed a system that mimicked the brain like substrate stiffness by using collagen coated polyacrylamide-based substrate whose stiffness can be modified from normal brain (0.5kPa) to tumorigenic (10kPa). Using these substrates, we were able to capture the morphological and physiological differences between parent and recurrent GBM which were not evident on plastic surfaces (~1 GPa). On 0.5kPa, unlike circular parent cells, recurrent GBM cells showed two morphologies (circular and elongated). The recurrent cells growing on 0.5kPa also showed higher proliferation, invasion, migration and in-vivo tumorigenicity in orthotropic GBM mouse model, compared to parent cells. Furthermore, recurrent cells exhibited elevated velocity irrespective of substrate stiffness, which indicated that recurrent cells may possess inherent differential mechanosignalling ability which was reflected by higher expression of ECM proteins like Collagen IVA, MMP2 and MMP9. Moreover, mice brain injected with recurrent cells grown on 0.5kPa substrate showed higher Young’s modulus values suggesting that recurrent cells conditioned on 0.5kPa make the surrounding ECM stiffer. Importantly, inhibition of EGFR signaling, that is amplified with tissue stiffening in GBM resulted in decreased invasion, migration and proliferation in 0.5kPa recurrent cells, but interestingly survival remained unaffected, highlighting the importance of mimicking the physiological stiffness of the brain mimicking clinical scenario. Total RNA seq analysis of parent and recurrent cells grown on plastic and 0.5kPa substrate identified PLEKHA7 as significantly upregulated gene specifically in 0.5kPa recurrent sample. Higher protein expression of PLEKHA7 in recurrent GBM as compared to primary GBM was validated in patient biopsies. Accordingly, PLEKHA7 knockdown reduced invasion and survival of recurrent GBM cells. Together, these data provides a model system that captures the differential mechanosensing signals of primary and recurrent GBM cells and identifies a novel potential target specific for recurrent GBM.
2023-06-29 | E-MTAB-11293 | biostudies-arrayexpress
Project description:To investigate the influence of stiffness as a major Bruch's membrane characteristic on the RPE transcriptome and morphology. ARPE-19 cells were plated on soft or stiff polyacrylamide gels (PA gels) or standard tissue culture plastic (TCP). We then performed gene expression profiling analysis using data obtained from Next-generation sequencing of small RNAs of ARPE-19 cells cultured on 3 different biomechanical conditions.
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Project description:To investigate the influence of stiffness as a major Bruch's membrane characteristic on the RPE transcriptome and morphology. ARPE-19 cells were plated on soft or stiff polyacrylamide gels (PA gels) or standard tissue culture plastic (TCP). We then performed gene expression profiling analysis using data obtained from Next-generation sequencing of small RNAs of ARPE-19 cells cultured on 3 different biomechanical conditions.
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Project description:Glioblastoma (GBM) bears a dismal prognosis with rapid relapse following complete resection and radiochemotherapy. The involvement of microRNAs in tumor progression has been demonstrated in hepatoma, breast cancer, and prostate cancers. However, the microRNAs involved in modulating the progression and relapse of GBM are still unclear. Initially, we compared the miRNA expression profiles between primary and recurrent GBM tissues from the same patient in twelve independent cases. miRNA expression profiles between primary and recurrent GBM tissues from the same patient in twelve independent cases.
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Project description:In vitro cultures of primary cardiac fibroblasts (CFs), the major extracellular matrix (ECM)-producing cells of the heart, are used to determine molecular mechanisms of cardiac fibrosis. However, the supraphysiologic stiffness of tissue culture polystyrene (TCPS) automatically triggers the conversion of CFs into an activated myofibroblast-like state, and serial passage of the cells results in the induction of replicative senescence. These dramatic phenotypic switches confound interpretation of experimental data obtained with cultured CFs. In an attempt to circumvent TCPS-induced activation and senescence of CFs, we utilized poly (ethylene glycol) (PEG) hydrogels as cell culture platforms with low and high stiffness formulations to mimic healthy and fibrotic cardiac ECM, respectively. As hypothesized, low hydrogel stiffness converted activated CFs into a quiescent state with reduced abundance of a-smooth muscle actin (a-SMA)-containing stress fibers. Unexpectedly, lower substrate stiffness concomitantly augmented CF senescence, marked by elevated senescence-associated b-galactosidase (SA-b-Gal) activity and increased expression of p16 and p21, which are cyclin-dependent kinase (CDK) inhibitors and markers of senescence. Using dynamically stiffening hydrogels with phototunable crosslinking capabilities, we demonstrate that substrate-induced CF senescence is partially reversible. RNA-sequencing analysis revealed widespread transcriptional reprogramming of CFs cultured on low stiffness hydrogels, with a dramatic reduction in the expression of profibrotic genes encoding ECM proteins, and an attendant increase in expression of NF-kB-responsive inflammatory genes that typify the senescence-associated secretory phenotype (SASP). Our findings further demonstrate that alterations in matrix stiffness profoundly impact CF cell state transitions, and suggest mechanisms by which CFs change phenotype in vivo depending on the stiffness of the myocardial microenvironment to which they are exposed.
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Project description:Mechanical feedback from the tumor microenvironment regulates an array of processes underlying cancer biology. Routine culture and adaptation of cancer cell lines to unnaturally rigid plastic or glass substrates leads to profound changes in their growth, metastatic potential and potentially chemotherapeutic response. Microarray studies were conducted to probe the impact of substratum stiffness on the regulation of genetic pathways in mammary tumor cells, and immortalized cancer cell lines, that modulate sensitivity and resistance towards clinically-approved chemotherapeutics We used microarrays to detail the global programme of gene expression underlying cellular response to substrates of different mechanical stiffness.
2019-03-28 | GSE107063 | GEO
Project description:Glioblastoma (GBM) bears a dismal prognosis with rapid relapse following complete resection and radiochemotherapy. The involvement of microRNAs in tumor progression has been demonstrated in hepatoma, breast cancer, and prostate cancers. However, the microRNAs involved in modulating the progression and relapse of GBM are still unclear. Initially, we compared the miRNA expression profiles between primary and recurrent GBM tissues from the same patient in twelve independent cases.
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Project description:Induced pluripotent stem cells were differentiated to brain microvascular endothelial-like (BMEC-like) cells and cultured on hydrogel substrates of varying stiffness. Cellular changes were measured by bulk transcriptome and proteome readouts.
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Project description:The substrate stiffness plays an important role in mediating the cellular behavior. Neutrophils predominate the early inflammatory response and initiate the regeneration. The neutrophil activation can be regulated by physical cues. However, it is not known how neutrophils respond to substrate stiffness, which is of significant importance in determining the outcomes of engineered tissue mimics. Herein, a three-dimensional culture system made of hydrogel for bone marrow-derived neutrophils was developed to explore the effects of varying stiffness (1.5, 2.6, and 5.7 kPa) on neutrophil phenotype and polarization states.
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Project description:Purpose: Identify the effect of substrate stiffness on gene expression Methods:Evaluating for differentially expressed mRNAs in the SKOV-3 cells grown on the different substrates via High-throughput sequence Results: We found that the general direction of changes in gene expression of cells grown on the different substrates and the most significant signalling pathways and the expression of gene orthologs broadly involved in platinum drug resistance, apoptosis, cell cycle. Conclusions: Our study represents the first detailed analysis of the effects of substrate stiffness on gene expression of ovarian cancer cells.
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