Drugless Extracellular Hydrogels Enable the Reprogramming of Malignant Glioblastoma
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE278415 | GEO | 2025/05/05
REPOSITORIES: GEO
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Project description:Background: Glioblastoma multiforme (GBM) is the most aggressive and most lethal primary malignant brain tumor, correlated with survival rates of less than one year from the time of diagnosis. Current surgical procedure attempts to remove the bulk of the tumor mass, whereas GBM frequently recurs within 1-3cm from the primary tumor resection site. Molecular mechanisms involved in the recurrence of the tumor are still poorly understood. The aim of the study was to define the molecular signature of GBM surrounding white matter (WM) in order to better understand the molecular mechanisms involved with tumor relapse. Material & Methods: Human GBM tumor bulk and surrounding tissue (1-3cm from the border of the tumor) were obtained from five patients who underwent total tumour resection, while normal white matter was harvested from patients who underwent surgical procedure for nonmalignant pathologies. Samples were processed for hybridization on the Affymetrix Human U133A arrays and data were examined with the GeneSpring analysis software. Results: Gene expression analysis of the samples was done in 2 independent steps. First, molecular profiling comparison of GBM surrounding WM and normal WM resulted in 59 genes differentially expressed between both tissues. Among these, numerous genes expressed by mature neural cells were down-regulated in GBM surrounding WM, while gene products supporting invasion were overexpressed. Moreover, KLRC1, a specific natural killer receptor naturally involved in the activation of antitumoral cells was drastically repressed in GBM surrounding WM, suggesting that the antitumoral immune surveillance is compromised in this tissue. Second, we focused our study on genes specifically regulated in GBM periphery respectively to GBM core. The highest up-regulated gene in GBM surrounding tissue encodes for DTX4, a regulator of NOTCH signalling pathway described for its key role in maintaining neural progenitors in an uncommitted state. Conclusion: This study revealed unique molecular characteristics of GBM surrounding tissue, showing the dysregulation of genes involved in immune surveillance along with genes associated to stemness maintenance. All together, these data may help to understand the molecular mechanisms associated with GBM recurrence This study attempted to define the molecular characteristics of the GBM surrounding tissue. To this end, GBM tumor samples were obtained from 5 patients who underwent total tumor resection. Surrounding tumor mass tissue was retrieved in all cases from not infiltrated white matter sited at 2 cm from the macroscopic tumor border. Furthermore, control white matter biopsies were harvested from patients operated on for deep intracerebral cavernomas. Each sample was hybridized onto Affymetrix human U133 arrays. For each patient, tumor core sample and surrounding tissue were harvested and are identified with the same suffix number. In 2 cases, (patients 3 and 4), two tumor peripheral tissue samples were harvested and are identified with the same number followed by "R" (replicate).
2009-06-15 | E-GEOD-13276 | biostudies-arrayexpress
Project description:Glioblastoma Multiforme (GBM) is the primary brain tumor with the highest incident and mortality rates worldwide. This is because therapies are not effective, mainly due to tumor recurrence after surgical resection and chemotherapeutic treatment. Recurrence is mainly produced by a tumoral cell sub-population called Glioblastoma Stem-like Cells (GSCs), which are primarily responsible for chemo-resistance and tumor infiltration. We previously showed that in this sub-population, adenosine regulates chemo-resistance through its A3AR. The importance of this study lies in the confirmation that the adenosine/A3AR axis is a plausible therapeutic target to attack different features of GBM, including chemo-resistance and cell migration/invasion of GSCs.
2019-05-06 | GSE100146 | GEO
Project description:Delivery of therapeutic stem cells to treat bone tissue damage is a promising strategy that faces many hurdles to clinical translation. Among them is the design of a delivery vehicle which promotes desired cell behavior for new bone formation. In this work, we describe the use of an injectable microporous hydrogel, made of crosslinked gelatin microgels, for the encapsulation and delivery of human mesenchymal stem cells (MSCs) and compared it to a traditional nonporous injectable hydrogel. MSCs encapsulated in the microporous hydrogel showed rapid cell spreading with direct cell-cell connections whereas the MSCs in the nonporous hydrogel were entrapped by the surrounding polymer mesh and isolated from each other. Microporous hydrogel induced more robust osteogenic differentiation of MSCs and calcium mineral deposition than the nonporous hydrogel confirmed by alkaline phosphatase (ALP) assay and calcium assay. RNA-seq confirmed the upregulation of the genes and pathways that are associated with cell spreading and cell-cell connections, as well as the osteogenesis in the microporous hydrogel. These results demonstrate that the microgel-based injectable hydrogels can be useful tools for therapeutic cell delivery for bone tissue repair.
2024-04-15 | GSE263939 | GEO
Project description:Background: Glioblastoma multiforme (GBM) is the most aggressive and most lethal primary malignant brain tumor, correlated with survival rates of less than one year from the time of diagnosis. Current surgical procedure attempts to remove the bulk of the tumor mass, whereas GBM frequently recurs within 1-3cm from the primary tumor resection site. Molecular mechanisms involved in the recurrence of the tumor are still poorly understood. The aim of the study was to define the molecular signature of GBM surrounding white matter (WM) in order to better understand the molecular mechanisms involved with tumor relapse. Material & Methods: Human GBM tumor bulk and surrounding tissue (1-3cm from the border of the tumor) were obtained from five patients who underwent total tumour resection, while normal white matter was harvested from patients who underwent surgical procedure for nonmalignant pathologies. Samples were processed for hybridization on the Affymetrix Human U133A arrays and data were examined with the GeneSpring analysis software. Results: Gene expression analysis of the samples was done in 2 independent steps. First, molecular profiling comparison of GBM surrounding WM and normal WM resulted in 59 genes differentially expressed between both tissues. Among these, numerous genes expressed by mature neural cells were down-regulated in GBM surrounding WM, while gene products supporting invasion were overexpressed. Moreover, KLRC1, a specific natural killer receptor naturally involved in the activation of antitumoral cells was drastically repressed in GBM surrounding WM, suggesting that the antitumoral immune surveillance is compromised in this tissue. Second, we focused our study on genes specifically regulated in GBM periphery respectively to GBM core. The highest up-regulated gene in GBM surrounding tissue encodes for DTX4, a regulator of NOTCH signalling pathway described for its key role in maintaining neural progenitors in an uncommitted state. Conclusion: This study revealed unique molecular characteristics of GBM surrounding tissue, showing the dysregulation of genes involved in immune surveillance along with genes associated to stemness maintenance. All together, these data may help to understand the molecular mechanisms associated with GBM recurrence
2009-06-15 | GSE13276 | GEO
Project description:Despite currently available treatment, the prognosis of patients with glioblastoma (GBM) is poor and recurrence is inevitable. Several new systemic treatment strategies have been evaluated in the past two decades, but most of those revealed disappointing results. Especially, newly developed tyrosine kinase inhbitors (TKIs) have been studied extensively. These agents inhibit intracellular signaling, i.e. tyrosine kinases, that exert a variety of biological activities, including cell proliferation and migration, and play an important role in GBM. Clinical trials evaluating TKIs have been evaluated for recurrent GBM resulted in minimal improvement in progression-free survival and no overall survival benefit, despite clinical significant benefit in other malignancies such as renal cell cancer. Whether these disappointing results are due to a restricted drug delivery of TKIs through the blood-brain barrier, or due to differential biological characteristics of GBM compared to other malignancies is unknown. MS-based phosphoproteomics was used as an approach for molecular tumor profiling to obtain insight into aberrantly activated signaling pathways and potential drug targets. The objective was to test the feasibility of determining the (phospho)proteomic profiles and kinase activity profiles in tumor tissue by mass spectrometry (MS) after treatment for 10 to 14 days. These profiles were compared to tumor tissue of a control group of patients with newly-diagnosed GBM, who were treated with a resection only.
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Project description:Clinical outcomes for patients with glioblastoma (GBM) are extremely poor due to inevitable tumor recurrence even after extensive treatments. These recurrences are thought to manifest from cells located within the tumor edge. Despite this, the precise molecular mechanism governing GBM spatial phenotypic heterogeneity (e.g. edge vs. core) and subsequent tumor recurrence remains poorly elucidated. Here, using patient-derived GBM core and edge tissues, we analyzed transcriptional and metabolic signatures in an effort to determine how GBM facilitates the edge phenotype and its associated recurrence-initiating cells (RICs). In so doing, we unexpectedly identified CD38 as an essential protein in the formation of the edge phenotype and found a CD38-driven interaction between edge GBM cells and neighboring astrocytes that communally develops a GBM edge that is unresectable by surgery and retains RICs.
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Project description:The discectomy-induced ferroptosis stress on nucleus pulposus cells (NPCs) is a major cause for postoperative lumbar disc herniation (LDH) recurrence and intervertebral disc degeneration (IDD). Surprisingly, we discovered that nucleus pulposus progenitor cells (NPPCs) could transmit their ferroptosis-resistant phenotype to recipient NPCs through exosome-dependent cell-cell communication while identifying miR-221-3p as the primary anti-ferroptosis effector molecule therein. Based on these findings, we first developed a synthetically-tailored NPPC-derived exosomes with enhanced miR-221-3p expression and NPC uptake capacity through molecular and cellular engineering, which were then integrated into an injectable hydrogel based on extracellular matrix (ECM) analogues. The ECM-mimetic hydrogel (HACS) serves as a biomimetic filler for the post-operative care of herniated discs, which could be facilely injected into the discectomy-established nucleus pulposus (NP) cavity for localized treatment. HACS-mediated in-situ exosome release in the NP cavity enabled marked ferroptosis inhibition in NPCs that not only prevented LDH recurrence but also reversed the IDD symptoms, leading to robust restoration of NP structure and functions. This study offers a promising approach for the treatment of herniated discs with translational potential.
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Project description:The discectomy-induced ferroptosis stress on nucleus pulposus cells (NPCs) is a major cause for postoperative lumbar disc herniation (LDH) recurrence and intervertebral disc degeneration (IDD). Surprisingly, we discovered that nucleus pulposus progenitor cells (NPPCs) could transmit their ferroptosis-resistant phenotype to recipient NPCs through exosome-dependent cell-cell communication while identifying miR-221-3p as the primary anti-ferroptosis effector molecule therein. Based on these findings, we first developed a synthetically-tailored NPPC-derived exosomes with enhanced miR-221-3p expression and NPC uptake capacity through molecular and cellular engineering, which were then integrated into an injectable hydrogel based on extracellular matrix (ECM) analogues. The ECM-mimetic hydrogel (HACS) serves as a biomimetic filler for the post-operative care of herniated discs, which could be facilely injected into the discectomy-established nucleus pulposus (NP) cavity for localized treatment. HACS-mediated in-situ exosome release in the NP cavity enabled marked ferroptosis inhibition in NPCs that not only prevented LDH recurrence but also reversed the IDD symptoms, leading to robust restoration of NP structure and functions. This study offers a promising approach for the treatment of herniated discs with translational potential.
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