TAMI-71. EFFECTS OF THE TREATED MICROENVIRONMENT ON GLIOMA CELL PROPERTIES IN AN ORGANOTYPIC BRAIN SLICE MODEL

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi213-vi213
Author(s):  
Vasiliki Pantazopoulou ◽  
Tracy Berg ◽  
Alexander Pietras
Keyword(s):  
Tumor Cells ◽  
Glioma Cell ◽  
Radiation Treatment ◽  
Ex Vivo ◽  
Brain Slices ◽  
Glioma Cells ◽  
Cell Phenotype ◽  
Slice Culture ◽  
Tumor Bearing ◽  
Organotypic Brain Slices

Abstract Glioblastoma is the most aggressive primary brain tumor. Despite treatment all patients invariably recur. Treatment resistance is attributed to the presence of glioma stem-like cells. Initially thought to be a distinct and static cell population, it is becoming increasingly clear that the glioma stem-like cell phenotype represents one of many cellular states and that glioma cells show plasticity between stem-like and non-stem like states. These plastic cell states are affected by the tumor microenvironment. In our lab we have shown that irradiated and hypoxic astrocytes increase the stem-like cell properties of glioma cells. In this study, we aim to evaluate how the treated microenvironment alters glioma cell properties and use ex vivo organotypic brain slices generated from tumor bearing and tumor naïve mice to assess all aspects of the microenvironment. We first characterized organotypic brain slices cultured in different oxygen tensions. We saw that tumor-bearing slices survive for at least 14 days in culture at 21%, 5% or 1% oxygen tension (O2). Tumor cells were more viable in all culture conditions and timepoints compared to non-tumor cells. Moreover, we found that astrocytes seem to be attracted to tumor areas in both 5% and 1% O2 cultures. We then used the organotypic glioma slice culture system to address how preconditioning the microenvironment using radiation or temozolomide affects the properties of glioma cells that are seeded in these pretreated, tumor naïve slices. We saw that fluorescently labelled glioma cells seeded in treated slices can be isolated after two days of culture in the slices and can be used for downstream analyses, such as temozolomide or radiation treatment and colony formation. This study will elucidate the effect of the treated microenvironment on glioma cell properties by using the medium throughput method of organotypic slice cultures.

scholarly journals TAMI-28. DIFFERENTIAL MIGRATION MECHANICS AND IMMUNE RESPONSES OF GLIOMA SUBTYPES

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii219-ii219
Author(s):  
Ghaidan Shamsan ◽  
Chao Liu ◽  
Brooke Braman ◽  
Susan Rathe ◽  
Aaron Sarver ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Immune Cell ◽  
Molecular Subtypes ◽  
Ex Vivo ◽  
Brain Slices ◽  
Traction Force ◽  
Genetic Alterations ◽  
Sleeping Beauty ◽  
Brain Parenchyma ◽  
Biophysical Modeling

Abstract In Glioblastoma (GBM), tumor spreading is driven by tumor cells’ ability to infiltrate healthy brain parenchyma, which prevents complete surgical resection and contributes to tumor recurrence. GBM molecular subtypes, classical, proneural and mesenchymal, were shown to strongly correlate with specific genetic alterations (Mesenchymal: NF1; Classical: EGFRVIII; Proneural: PDGFRA). Here we tested the hypothesis that a key mechanistic difference between GBM molecular subtypes is that proneural cells are slow migrating and mesenchymal cells are fast migrating. Using Sleeping Beauty transposon system, immune-competent murine brain tumors were induced by SV40-LgT antigen in combination with either NRASG12V (NRAS) or PDGFB (PDGF) overexpression. Cross-species transcriptomic analysis revealed NRAS and PDGF-driven tumors correlate with human mesenchymal and proneural GBM, respectively. Similar to human GBM, CD44 expression was higher in NRAS tumors and, consistent with migration simulations of varying CD44 levels, ex vivo brain slice live imaging showed NRAS tumors cells migrate faster than PDGF tumors cells (random motility coefficient = 30µm2/hr vs. 2.5µm2/hr, p < 0.001). Consistent with CD44 function as an adhesion molecule, migration phenotype was independent of the tumor microenvironment. NRAS and human PDX/MES tumor cells were found to migrate faster and have larger cell spread area than PDGF and human PDX/PN tumors cells, respectively, in healthy mouse brain slices. Furthermore, traction force microscopy revealed NRAS tumor cells generate larger traction forces than PDGF tumors cells which further supports our theoretical mechanism driving glioma migration. Despite increased migration, NRAS cohort had better survival than PDGF which was attributed to enhanced antitumoral immune response in NRAS tumors, consistent with increased immune cell infiltration found in human mesenchymal GBM. Overall our work identified a potentially actionable difference in migration mechanics between GBM subtypes and establishes an integrated biophysical modeling and experimental approach to mechanically parameterize and simulate distinct molecular subtypes in preclinical models of cancer.

Enhancement of radiosensitivity of wild-type p53 human glioma cells by adenovirus-mediated delivery of the p53 gene

1998 ◽  
Vol 89 (1) ◽  
pp. 125-132 ◽  
Author(s):  
Frederick F. Lang ◽  
W. K. Alfred Yung ◽  
Uma Raju ◽  
Floralyn Libunao ◽  
Nicholas H. A. Terry ◽  
...  
Keyword(s):  
Cell Line ◽  
Glioma Cell ◽  
Radiation Treatment ◽  
P53 Protein ◽  
Glioma Cells ◽  
Glioma Cell Line ◽  
Wild Type ◽  
Content Type ◽  
Infected Cells ◽  
Fine Print

Object. The authors sought to determine whether combining p53 gene transfer with radiation therapy would enhance the therapeutic killing of p53 wild-type glioma cells. It has been shown in several reports that adenovirus-mediated delivery of the p53 gene into p53 mutant gliomas results in dramatic apoptosis, but has little effect on gliomas containing wild-type p53 alleles. Therefore, p53 gene therapy alone may not be a clinically effective treatment for gliomas because most gliomas are composed of both p53 mutant and wild-type cell populations. One potential approach to overcome this problem is to exploit the role p53 plays as an important determinant in the cellular response to ionizing radiation. Methods. In vitro experiments were performed using the glioma cell line U87MG, which contains wild-type p53. Comparisons were made to the glioma cell line U251MG, which contains a mutant p53 allele. Monolayer cultures were infected with an adenovirus containing wild-type p53 (Ad5CMV-p53), a control vector (dl312), or Dulbecco's modified Eagle's medium (DMEM). Two days later, cultures were irradiated and colony-forming efficiency was determined. Transfection with p53 had only a minor effect on the plating efficiency of nonirradiated U87MG cells, reducing the plating efficiency from 0.23 ± 0.01 in DMEM to 0.22 ± 0.04 after addition of Ad5CMV-p53. However, p53 transfection significantly enhanced the radiosensitivity of these cells. The dose enhancement factor at a surviving fraction of 0.10 was 1.5, and the surviving fraction at 2 Gy was reduced from 0.61 in untransfected controls to 0.38 in p53-transfected cells. Transfection of the viral vector control (dl312) had no effect on U87MG radiosensitivity. In comparison, transfection of Ad5CMV-p53 into the p53 mutant cell line U251MG resulted in a significant decrease in the surviving fraction of these cells compared with controls, and no radiosensitization was detected. To determine whether Ad5CMV-p53—mediated radiosensitization of U87MG cells involved an increase in the propensity of these cells to undergo apoptosis, flow cytometric analysis of terminal deoxynucleotidyl transferase-mediated biotinylated-deoxyuridinetriphosphate nick-end labeling—stained cells was performed. Whereas the amount of radiation-induced apoptosis in uninfected and dl312-infected control cells was relatively small (2.1 ± 0.05% and 3.7 ± 0.5%, respectively), the combination of Ad5CMV-p53 infection and radiation treatment significantly increased the apoptotic frequency (18.6 ± 1.4%). To determine whether infection with Ad5CMV-p53 resulted in increased expression of functional exogenous p53 protein, Western blot analysis of p53 was performed on U87MG cells that were exposed to 9 Gy of radiation 2 days after exposure to Ad5CMV-p53, dl312, or DMEM. Infection with Ad5CMV-p53 alone increased p53 levels compared with DMEM- or dl312-treated cells. Irradiation of Ad5CMV-p53—infected cells resulted in a further increase in p53 that reached a maximum at 2 hours postirradiation. To determine whether exogenous p53 provided by Ad5CMV-p53 had transactivating activity, U87MG cells were treated as described earlier and p21 messenger RNA levels were determined. Infection of U87MG cells with Ad5CMV-p53 only resulted in an increase in p21 compared with DMEM- and dl312-treated cells. Irradiation of Ad5CMV-p53—infected cells resulted in an additional time-dependent increase in p21 expression. Conclusions. These data indicate that adenovirus-mediated delivery of p53 may enhance the radioresponse of brain tumor cells containing wild-type p53 and that this radiosensitization may involve converting from a clonogenic to the more sensitive apoptotic form of cell death. Although the mechanism underlying this enhanced apoptotic susceptibility is unknown, the Ad5CMV-p53—infected cells have a higher level of p53 protein, which increases further after irradiation, and this exogenous p53 is transcriptionally active. Thus, it is possible that the combination of Ad5CMV-p53 infection and radiation treatment increases p53 protein to a level that is sufficient to overcome at least partially the block in apoptosis existing in U87MG cells.

scholarly journals Multicellular ‘hotspots’ harbour high-grade potential in lower-grade gliomas

2021 ◽  
Author(s):  
Alastair J Kirby ◽  
José P Lavrador ◽  
Istvan Bodi ◽  
Francesco Vergani ◽  
Ranjeev Bhangoo ◽  
...  
Keyword(s):  
Human Brain ◽  
Brain Tissue ◽  
Aminolevulinic Acid ◽  
Ex Vivo ◽  
Brain Slices ◽  
Glioma Cells ◽  
Malignant Progression ◽  
Lower Grade ◽  
High Grade ◽  
Human Brain Tissue

Abstract Background Lower-grade gliomas may be indolent for many years before developing malignant behaviour. The reasons mechanisms underlying malignant progression remain unclear. Methods We collected blocks of live human brain tissue donated by people undergoing glioma resection. The tissue blocks extended through the peritumoral cortex and into the glioma. The living human brain tissue was cut into ex vivo brain slices and bathed in 5-aminolevulinic acid (5-ALA). High-grade glioma cells avidly take up 5-aminolevulinic acid (5-ALA) and accumulate high levels of the fluorescent metabolite, Protoporphyrin IX (PpIX). We exploited the PpIX fluorescence emitted by higher-grade glioma cells to investigate the earliest stages of malignant progression in lower-grade gliomas. Results We found sparsely-distributed ‘hot-spots’ of PpIX-positive cells in living lower-grade glioma tissue. Glioma cells and endothelial cells formed part of the PpIX hotspots. Glioma cells in PpIX hotspots were IDH1 mutant and expressed nestin suggesting they had acquired stem-like properties. Spatial analysis with 5-ALA conjugated quantum dots indicated that these glioma cells replicated adjacent to blood vessels. PpIX hotspots formed in the absence of angiogenesis. Conclusion Our data show that PpIX hotspots represent microdomains of cells with high-grade potential within lower-grade gliomas and identify locations where malignant progression could start.

scholarly journals Growth suppression of glioma cells using HDAC6 inhibitor, tubacin

Open Medicine ◽  
2018 ◽  
Vol 13 (1) ◽  
pp. 221-226 ◽  
Author(s):  
Changjiang Yin ◽  
Pibao Li
Keyword(s):  
Cancer Research ◽  
Glioma Cell ◽  
Alkylating Agent ◽  
Radiation Treatment ◽  
Combined Treatment ◽  
Specific Inhibitor ◽  
Glioma Cells ◽  
Histone Deacetylase 6 ◽  
Hdac6 Inhibitor

AbstractIn cancer research, autophagy has been revealed as one of the major ways to maintain the metabolism of cancer cells, including glioma cells, through protein degradation. Meanwhile, autophagy is also regarded as a kind of mechanism to protect glioma cells from a harmful stimulus, such as chemical and radiation treatment. So, the inhibition of autophagy may be very helpful in curing glioma. This study aimed to determine the effect of autophagic inhibition on glioma cells using tubacin, a specific inhibitor of histone deacetylase 6(HDAC6). According to the results, tubacin inhibited the growth of both U251 and LN229 cells, which was accompanied by lower HDAC6 activity and accumulated autophagosome. The inhibition of HDCA6 also led to accumulation of autophagosome and death of glioma cells. Moreover, the combined treatment of tubacin and temozolomide, an alkylating agent used to treat glioblastoma, induced more severe glioma cell death. Thus, it can be concluded that inhibition of HDAC6 suppressed growth and drug resistance of glioma cells in-vitro through autophagic suppression and blocking of fusion of autophagosome and lysosome.

Tumor necrosis factor–related apoptosis-inducing ligand–mediated apoptosis in established and primary glioma cell lines

2002 ◽  
Vol 13 (3) ◽  
pp. 1-11 ◽  
Author(s):  
Jay Jaganathan ◽  
Joshua H. Petit ◽  
Barbara E. Lazio ◽  
Satyendra K. Singh ◽  
Lawrence S. Chin
Keyword(s):  
Cell Death ◽  
Tumor Cells ◽  
Cell Lines ◽  
Glioma Cell ◽  
Apoptotic Cell ◽  
Glioma Cells ◽  
Trail Receptors ◽  
Glioma Cell Lines ◽  
Caspase 7 ◽  
U373 Cells

Object Tumor necrosis factor (TNF)–related apoptosis-inducing ligand (TRAIL) is a member of the TNF cytokine family, which mediates programmed cell death (apoptosis) selectively in tumor cells. The selective tumoricidal activity of TRAIL is believed to be modulated by agonistic (DR4 and DR5) and antagonistic receptors (DcR1 and DcR2), which appear to compete for ligand binding. Because TRAIL is expressed in a wide range of tissues, including brain, kidney, and spleen, and seems consistently to induce cell death in tumor cells, the cytokine has been identified as a promising approach for selectively inducing tumor cell death. In this study, the authors examine the importance of TRAIL's receptors in both its selectivity for tumor cells and its ability to induce apoptosis. Methods The authors first examined sensitivity to TRAIL and expression of TRAIL receptors in four established and four primary cultured glioma cell lines by using viability and fluorescent apoptosis assays. They then evaluated DR5 expression and JNK, caspase 3, and caspase 7 activation by conducting immunoblot analyses. Reverse transcriptase–polymerase chain reaction (RT-PCR) was performed to study expression of DR4, DR5, DcR1, and DcR2. The DR5 transcripts from one TRAIL-sensitive, one partially TRAIL-resistant, and one TRAIL-resistant cell line were subsequently sequenced. The expression of TRAIL receptors in normal and glial brain tumor pathological specimens were then compared using immunohistochemistry. Finally, to study the direct effects of DR5 on glioma cells, the authors conducted transient and stable transfections of the fulllength DR5 transcript into glioma cells with and without preestablished overexpression of the antiapoptotic gene bcl-2. The established glioma cell lines T98G and U87MG, and all primary cell lines, were apoptotic at greater than or equal to 100 ng/ml TRAIL. The A172 cells, by contrast, were susceptible only with cycloheximide, whereas U373MG cells were not susceptible to TRAIL. The JNK, caspase 3, and caspase 7 activity evaluated after treatment with TRAIL showed that TRAIL-sensitive cell lines exhibited downstream caspase activation, whereas TRAIL-resistant cells did not. The DR5 sequences in T98G, A172, and U373MG cell lines were identical to published sequences despite these differences in sensitivity to TRAIL. The RT-PCR performed on extracts from the eight glioma cell lines showed that all expressed DR5. Immunohistochemistry revealed ubiquitous expression of DR5 in glioma specimens, with an associated lack of decoy receptor expression. Normal brain specimens, by contrast, stained positive for both DR5 and DcR1. Overexpression of DR5 under both transfection conditions resulted in cell death in all three cell lines. The previously seen resistance of U373 cells to TRAIL was not observed. Apoptotic cell death was confirmed using DNA fragmentation in T98G cell lines and fluorescent miscroscopy in all cell lines. The T98G cells stably transfected with bcl-2 before DR5 overexpression were protected from cell death. Conclusions The authors conclude that DR5 represents a promising new approach to directly activating the intrinsic caspase pathway in glioma cells. The fact that TRAIL-resistant gliomas do not express decoy receptors suggests a mechanism of resistance unique from that proposed for normal tissues. The overexpression of DR5 induced apoptotic cell death in glioma cells without TRAIL and was able to overcome the resistance to TRAIL demonstrated in U373 cells. The Bcl-2 protects cells from DR5 by acting downstream of the receptor, most likely at the level of caspase activation.

scholarly journals Comparative dynamics of microglial and glioma cell motility at the infiltrative margin of brain tumours

2018 ◽  
Vol 15 (139) ◽  
pp. 20170582 ◽  
Author(s):  
Joseph Juliano ◽  
Orlando Gil ◽  
Andrea Hawkins-Daarud ◽  
Sonal Noticewala ◽  
Russell C. Rockne ◽  
...  
Keyword(s):  
Glioma Cell ◽  
Cell Tracking ◽  
Brain Slices ◽  
Cell Movement ◽  
Glioma Cells ◽  
Time Lapse ◽  
Simple Random Walk ◽  
Migratory Behaviour ◽  
Fluorescent Markers ◽  
Mathematical Techniques

Microglia are a major cellular component of gliomas, and abundant in the centre of the tumour and at the infiltrative margins. While glioma is a notoriously infiltrative disease, the dynamics of microglia and glioma migratory patterns have not been well characterized. To investigate the migratory behaviour of microglia and glioma cells at the infiltrative edge, we performed two-colour time-lapse fluorescence microscopy of brain slices generated from a platelet-derived growth factor-B (PDGFB)-driven rat model of glioma, in which glioma cells and microglia were each labelled with one of two different fluorescent markers. We used mathematical techniques to analyse glioma cells and microglia motility with both single cell tracking and particle image velocimetry (PIV). Our results show microglia motility is strongly correlated with the presence of glioma, while the correlation of the speeds of glioma cells and microglia was variable and weak. Additionally, we showed that microglia and glioma cells exhibit different types of diffusive migratory behaviour. Microglia movement fit a simple random walk, while glioma cell movement fits a super diffusion pattern. These results show that glioma cells stimulate microglia motility at the infiltrative margins, creating a correlation between the spatial distribution of glioma cells and the pattern of microglia motility.

scholarly journals DDIS-04. INTERFERON-β SENSITIZES HUMAN GLIOBLASTOMA CELLS TO THE CYCLIN-DEPENDENT KINASE INHIBITOR, TG02

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi65-vi66
Author(s):  
Emilie Le Rhun ◽  
Birthe Lohmann ◽  
Mirka Epskamp ◽  
Michael Weller
Keyword(s):  
Rna Polymerase Ii ◽  
Glioma Cell ◽  
Kinase Inhibitor ◽  
Synergistic Effects ◽  
Glioma Cells ◽  
Type I Interferons ◽  
Cell Phenotype ◽  
Type I ◽  
Cyclin Dependent Kinase ◽  
Human Glioma

Abstract Novel treatments for glioblastoma, the most common malignant primary brain tumor, are urgently needed. Type I interferons (IFN) are natural cytokines primarily involved in defense against viral infections, but may also play a role in the control of cancer, notably in the suppression of the cancer stem cell phenotype. TG02 is a novel orally available cyclin-dependent kinase 9 inhibitor which induces glioma cell apoptosis without profound caspase activation and is currently being explored in early clinical trials in newly diagnosed and recurrent glioblastoma. Here we used human glioma-initiating cell line models to explore whether IFN-β modulate the anti-glioma activity of TG02. Pre-exposure to IFN-β sensitized human glioma models to a variable extent to subsequent exposure to TG02. Combination treatment was associated with increased DEVD-amc cleaving activity that was blocked by BCL2. However, BCL2 did not protect from the synergistic effects of IFN and TG02 on glioma cell growth, furthermore, although IFN strongly induced pro-apoptotic XIAP-associated factor (XAF) expression, disrupting XAF expression did not abrogate the synergy with TG02 either. Consistent with that, caspase 3 gene silencing did not abrogate effects of TG02 or IFN-β alone or in combination. Finally, we observed that IFN-β may indeed modulate the effects of TG02 up-stream in the signaling cascade since inhibition of RNA polymerase II phosphorylation, a direct readout of TG02 pharmacodynamic activity, was facilitated in glioma cells pre-exposed to IFN-β. In summary, these data suggest that type I IFN may be combined with TG02 to limit glioblastoma growth but the well characterized effects of IFN and TG02 on apoptotic signaling are dispensable for synergistic control of tumor growth. Instead, exploring how IFN signaling primes glioma cells for TG02-mediated direct target inhibition may help to design novel, more effective pharmacological approaches to glioblastoma.

Effect of glycolysis inhibition by miR-448 on glioma radiosensitivity

2020 ◽  
Vol 132 (5) ◽  
pp. 1456-1464 ◽  
Author(s):  
Fengming Lan ◽  
Qing Qin ◽  
Huiming Yu ◽  
Xiao Yue
Keyword(s):  
Mouse Model ◽  
Cell Lines ◽  
Radiation Treatment ◽  
Glioma Cells ◽  
Luciferase Reporter ◽  
Bioinformatics Analyses ◽  
Subcutaneous Tumor ◽  
Tumor Bearing ◽  
U87 Cells

OBJECTIVEAlthough glucose metabolism reengineering is a typical feature of various tumors, including glioma, key regulators of glycolytic reprogramming are still poorly understood. The authors sought to investigate whether glycolysis inhibition by microRNA (miR)–448 increases radiosensitivity in glioma cells.METHODSThe authors used glioma tissue samples from glioma patients, cells from glioblastoma (GBM) cell lines and normal human astrocyte cells, and subcutaneous tumor–bearing U87 cells in mice to examine the effects of signaling regulation by miR-448 in the response of glioma tissues and cells to radiation treatment. Techniques used for investigation included bioinformatics analyses, biochemical assays, luciferase reporter assays, and establishment of subcutaneous tumors in a mouse model. Glucose consumption, LDH activity, and cellular ATP were measured to determine the ability of glioma cells to perform glycolysis. Expression of HIF-1α was measured as a potential target gene of miR-448 in glycolysis.RESULTSmiR-448 was detected and determined to be significantly downregulated in both glioma tissues from glioma patients and GBM cell lines. Furthermore, miR-448 acted as a tumor-inhibiting factor and suppressed glycolysis in glioma by negatively regulating the activity of HIF-1α signaling and then interfering with its downstream regulators relative to glycolysis, HK1, HK2, and LDHA. Interestingly, overexpression of miR-448 increased the x-radiation sensitivity of glioma cells. Finally, in in vivo experiments, subcutaneous tumor–bearing U87 cells in a mouse model verified that high expression of miR-448 also enhanced glioma radiosensitivity via inhibiting glycolytic factors.CONCLUSIONSmiR-448 can promote radiosensitivity by inhibiting HIF-1α signaling and then negatively controlling the glycolysis process in glioma. A newly identified miR-448–HIF-1α axis acts as a potentially valuable therapeutic target that may be useful in overcoming radioresistance in glioma treatment.

TAMI-30. THERAPY INDUCED REPROGRAMMING DRIVES GLIOMA VASCULAR TRANSDIFFERENTIATION AND TUMOR RECURRENCE

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi204-vi204
Author(s):  
Sree Deepthi Muthukrishnan ◽  
Riki Kawaguchi ◽  
Pooja Nair ◽  
Rachna Prasad ◽  
Alvaro Alvarado ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Tumor Cells ◽  
Tumor Recurrence ◽  
Radiation Treatment ◽  
Glioma Cells ◽  
Chromatin Accessibility ◽  
Phenotype Switch ◽  
Aggressive Tumor ◽  
Functional States ◽  
Histone Acetyltransferase Activity

Abstract Therapy-resistant glioma cells elicit phenotypic plasticity leading to aggressive tumor recurrence. Here, we employed single-cell and whole transcriptomic analyses to uncover that a standard glioma treatment, radiation induces a dynamic shift in functional states of glioma cells allowing for acquisition of mesenchymal-like and vascular-like phenotypes. The predominant phenotype switch induced by radiation in surviving tumor cells is transdifferentiation to endothelial-like and pericyte-like cells. The transdifferentiated cells in turn promote proliferation of radiated tumor cells, and their selective depletion results in reduced tumor growth and recurrence post-treatment. The acquisition of vascular-like phenotype is driven by increased chromatin accessibility in vascular genes, and blocking P300-mediated histone acetyltransferase activity prior to radiation treatment inhibits vascular transdifferentiation and tumor growth. Our findings indicate that radiation therapy reprograms tumor cells driving vascular transdifferentiation, and highlights HAT inhibitors as potential therapeutic target for preventing GBM relapse

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