Glioblastoma Drives Protease-Independent Extracellular Matrix Invasion of Microglia DOI
C.-S. Chang, Ashwin Bale, Rohit Bhargava

et al.

Published: Nov. 11, 2024

Glioblastoma (GBM) is the most common and lethal form of primary brain cancer. Microglia infiltration into tumor microenvironment associated with immunosuppression poor prognosis. Improved physicochemical understanding microglia activation invasion may provide novel GBM therapeutic strategies essential for improving long-term treatment efficacy. Here, we combine microfluidic systems 3-D collagen hydrogels to systematically investigate activation, invasion, contractility cytokine secretion in response GBM-microglia crosstalk. inflammatory biomolecules significantly promote 3D microglia. Interestingly, not affected by inhibitors MMP activity or cellular glycolysis. In contrast, ROCK-pathway inhibition impedes invasion. Infrared microscopy analyses show that co-culture does alter lipid content. Further, conditioned media resulted increased hydrogel contraction, suggesting importance physically remodel local extracellular matrix (ECM). We also identify a panel soluble proteins contribute chemotaxis, such as TIMP-1 CXCL12. Taken together, this study suggests presence cells can enhance via contractility, independent

Language: Английский

Identification of Prognostic Genes Related to Cell Senescence and Lipid Metabolism in Glioblastoma Based on Transcriptome and Single-Cell RNA-Seq Data DOI Open Access

Qiong Li,

Hongde Liu

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(5), P. 1875 - 1875

Published: Feb. 21, 2025

Glioblastoma (GBM) is the most aggressive primary brain cancer, with poor prognosis due to its behavior and high heterogeneity. This study aimed identify cellular senescence (CS) lipid metabolism (LM)-related prognostic genes improve GBM treatment. Transcriptome scRNA-seq data, CS-associated (CSAGs), LM-related (LMRGs) were acquired from public databases. Prognostic identified by intersecting CSAGs, LMRGs, differentially expressed (DEGs), followed WGCNA univariate Cox regression. A risk model nomogram constructed. Analyses covered clinicopathological features, immune microenvironment, somatic mutations, drug sensitivity. data key cells gene expression. SOCS1 PHB2 as markers, contributing construction of a robust excellent predictive ability. High-risk group (HRG) patients had poorer survival, higher stromal scores, distinct mutation profiles. Drug sensitivity analysis revealed significant differences in IC50 values. In microglia differentiation, showed dynamic expression patterns. These findings provide new strategies for

Language: Английский

Citations

0
Radiation damage to a three-dimensional hydrogel model of the brain perivascular niche DOI Creative Commons

Yoanna Ivanova,

Alison C. Nunes, J. Virgílio Cruz

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 26, 2025

Glioblastoma (GBM) is a highly aggressive and recurrent brain cancer characterized by diffuse metastasis at the tumor margins. Radiation therapy standard component of current treatment offers potential for improved patient outcomes. While radiation targets GBM cells in margins, it may also significantly damage adjacent non-cancerous tissues, leading to reduced quality life potentially creating tumor-supportive microenvironment. The perivascular niche (PVN) margins believed play significant role regulating glioblastoma stem cell subpopulation as well serving site recurrence migration. Understanding impact on PVN can better inform schemes improve our understanding recurrence, but difficult vivo . Here we adapt previously developed three-dimensional hydrogel model investigate dosage delivery rate properties vitro Effects vessel architecture be measured this hydrogel-based model, suggesting an approach that provide insight into effects shorter time scale relative experiments. plays progression target therapy. We report method use models benchmark This provides new

Language: Английский

Citations

0
Targeting the DNA damage response in cancer DOI Creative Commons

Guffanti Federica,

Chiappa Michela,

Giovanna Damia

et al.

MedComm, Journal Year: 2024, Volume and Issue: 5(11)

Published: Oct. 31, 2024

DNA damage response (DDR) pathway is the coordinated cellular network dealing with identification, signaling, and repair of damage. It tightly regulates cell cycle progression promotes to minimize daughter cells. Key proteins involved in DDR are frequently mutated/inactivated human cancers promote genomic instability, a recognized hallmark cancer. Besides being an intrinsic property tumors, also represents unique therapeutic opportunity. Indeed, inhibition expected delay repair, causing persistent unrepaired breaks, interfere progression, sensitize cancer cells several DNA-damaging agents, such as radiotherapy chemotherapy. In addition, defects have been shown render these more dependent on remaining pathways, which could be targeted very specifically (synthetic lethal approach). Research over past two decades has led synthesis testing hundreds small inhibitors against key proteins, some antitumor activity cancers. parallel, search for synthetic lethality interaction broadening use inhibitors. this review, we discuss state-of-art ataxia-telangiectasia mutated, ataxia-telangiectasia-and-Rad3-related protein, checkpoint kinase 1, Wee1 Polθ inhibitors, highlighting results obtained ongoing clinical trials both monotherapy combination chemotherapy radiotherapy.

Language: Английский

Citations

4
Progress of ATM inhibitors: opportunities and challenges DOI

Shan Du,

Qi Liang,

Jianyou Shi

et al.

European Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 277, P. 116781 - 116781

Published: Aug. 15, 2024

Language: Английский

Citations

2
Inhibition of H3K27M-enhanced ATM signaling increases radiation efficacy in diffuse midline glioma DOI Open Access
Erik Peterson, Leslie A. Parsels,

Joshua D. Parsels

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 3, 2024

ABSTRACT H3K27-altered diffuse midline glioma (DMG) is an aggressive and treatment-resistant form of pediatric high-grade (pHGG). The disease defined by point mutations in histone H3 that convert lysine 27 to methionine (termed H3K27M), resulting genome-wide epigenetic changes drive tumorigenesis. While radiation therapy the standard care, subsequent recurrence, often within high dose field, universal. We found apical DNA damage response (DDR) kinase Ataxia Telangiectasia-Mutated (ATM) was uniquely upregulated H3K27M-expressing patient tumor samples compared pHGG expressing only wild-type H3. Using a panel H3K27 isogenic DMG cell lines, we further H3K27M associated with reduced H3K27me 3 ATM promoter, increased mRNA levels, elevated DDR signaling, even absence exogenous damage. Consistent these results, AZD1390, clinical-grade, CNS-penetrant inhibitor, sensitized neurospheres long-term effects on survival, part due attenuated repair radiation-induced Finally, AZD1390 orthotopic mutant tumors radiotherapy significantly extended median survival relative vehicle, or alone (50 days vs 31, 36 39 days, respectively) minimal adverse effects. Taken together, data provide direct mechanistic link between mutation expression support clinical investigation H3K27M-altered DMG.

Language: Английский

Citations

0
Current trends and future perspectives in hadron therapy: radiobiology DOI Creative Commons
Michael D. Story, Anthony J. Davis, Brock J. Sishc

et al.

Health and Technology, Journal Year: 2024, Volume and Issue: 14(5), P. 867 - 872

Published: July 15, 2024

Abstract Purpose The purpose of this article was to highlight current and future trends in radiobiology an effort move hadron therapy forward through the application new knowledge DNA damage subsequent response heavy ion radiotherapy, immune oncology interconnection between. Methods subject matter begins with a description role radiation eliciting either immunogenic or tolerogenic exposure. fragmented is described, followed by definitive that repair, not, complex after exposure plays survival irradiated cells. Results process which ionizing elicits rather than becoming clearer. timing fractionated radiotherapy when combined checkpoint inhibitor not clear may be tumor site specific. Furthermore, whether more effective at generating durable unknown. Conclusions Cytosolic significant innate likelihood would generate because it less likely repaired, become cytosolic DNA, activate response. Lastly, repair pathway choice appears credible bio-indicator for selection as well identify druggable targets enhance therapy.

Language: Английский

Citations

0
ATM Kinase Small Molecule Inhibitors Prevent Radiation-Induced Apoptosis of Mouse Neurons In Vivo DOI Creative Commons
Yüksel Aydar,

Sanara S. Rambukkanage,

Lauryn Brown

et al.

Kinases and Phosphatases, Journal Year: 2024, Volume and Issue: 2(3), P. 268 - 278

Published: Sept. 18, 2024

ATM kinase is becoming an important therapeutic target for tumor radiosensitization. Radiation known to cause neuro-inflammation and neurodegeneration; however, the effects of small molecule inhibitors (ATMi’s) radiation on normal tissue, including healthy brain, are largely unexplored. Therefore, we examined mouse CNS after ATMi radiosensitization with a focus fate neurons. We used several approaches assess DNA damage response (DDR) apoptosis neurons using immunostaining. In vivo, significant decrease in viable increase degenerating was observed mice treated alone. On other hand, alone had little no effect neuron viability did not induce apoptosis. Importantly, ATMi’s further toxicity. fact, multiplex immunostaining showed that clinical candidate (AZD1390) protected from by 90% at 4 h radiation. speculate lack toxicity due ATM–p53 that, if blocked transiently ATMi, protective. Altogether, line previous work knockout mice, provide evidence inhibition molecules does add neuronal toxicity, might, protect them radiation-induced least short term.

Language: Английский

Citations

0
New insight into targeting the DNA damage response in the treatment of glioblastoma DOI
Tao Zhen, Tianyu Sun, Bin Xiong

et al.

Chinese Journal of Natural Medicines, Journal Year: 2024, Volume and Issue: 22(10), P. 869 - 886

Published: Oct. 1, 2024

Language: Английский

Citations

0
Glioblastoma Drives Protease-Independent Extracellular Matrix Invasion of Microglia DOI
C.-S. Chang, Ashwin Bale, Rohit Bhargava

et al.

Published: Nov. 11, 2024

Glioblastoma (GBM) is the most common and lethal form of primary brain cancer. Microglia infiltration into tumor microenvironment associated with immunosuppression poor prognosis. Improved physicochemical understanding microglia activation invasion may provide novel GBM therapeutic strategies essential for improving long-term treatment efficacy. Here, we combine microfluidic systems 3-D collagen hydrogels to systematically investigate activation, invasion, contractility cytokine secretion in response GBM-microglia crosstalk. inflammatory biomolecules significantly promote 3D microglia. Interestingly, not affected by inhibitors MMP activity or cellular glycolysis. In contrast, ROCK-pathway inhibition impedes invasion. Infrared microscopy analyses show that co-culture does alter lipid content. Further, conditioned media resulted increased hydrogel contraction, suggesting importance physically remodel local extracellular matrix (ECM). We also identify a panel soluble proteins contribute chemotaxis, such as TIMP-1 CXCL12. Taken together, this study suggests presence cells can enhance via contractility, independent

Language: Английский

Citations

0