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Tumor cell-intrinsic Piezo2 drives radioresistance by impairing CD8+ T cell stemness maintenance

ABSTRACT: Tumor cell-intrinsic Piezo2 drives radioresistance by impairing CD8+ T cell stemness maintenance

PROVIDER: PRJNA990662 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25114066_1.fastq.gz	Fastqsanger.gz
	SRR25114066_2.fastq.gz	Fastqsanger.gz
	SRR25114067_1.fastq.gz	Fastqsanger.gz
	SRR25114067_2.fastq.gz	Fastqsanger.gz
	SRR25114068_1.fastq.gz	Fastqsanger.gz

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Tumor cell-intrinsic Piezo2 drives radioresistance by impairing CD8+ T cell stemness maintenance

Project description:Piezo2 impedes stemness maintenance of CD8+ T cells by downregulating IL-15 production after radiotherapy, thereby leading to cancer radioresistance.

2024-08-08 | GSE236345 | GEO

Tumor cell-intrinsic Piezo2 drives radioresistance by impairing CD8+ T cell stemness maintenance

Project description:Piezo2 impedes stemness maintenance of CD8+ T cells by downregulating IL-15 production after radiotherapy, thereby leading to cancer radioresistance.

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Tumor cell-intrinsic Piezo2 drives radioresistance by impairing CD8+ T cell stemness maintenance

Project description:Tumor cell-intrinsic Piezo2 drives radioresistance by impairing CD8+ T cell stemness maintenance

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Multisite phosphorylation by protein kinase A mediates modality-specific modulation of PIEZO2

Project description:Protein kinase A is a downstream effector of many inflammatory mediators that induce pain hypersensitivity by increasing the mechanosensitivity of nociceptive sensory afferent. Here we examine the molecular mechanism underlying protein kinase-Adependent modulation of the mechanically-activated ion channel PIEZO2, which confers mechanosensitivity to many nociceptors. Using phosphorylation site prediction algorithms, we identified multiple putative and highly conserved PKA phosphorylation sites located on intracellular intrinsically disordered regions of PIEZO2. Site-directed mutagenesis and patch-clamp recordings showed that substitution of one or multiple putative PKA sites within a single intracellular domains does not alter PKA-induced PIEZO2 sensitization, whereas mutation of a combination of nine putative sites located on four different intracellular regions completely abolishes PKA-dependent PIEZO2 modulation, suggesting that the effect requires multisite phosphorylation. By demonstrating that PIEZO1 is not modulated by PKA, our data also reveals a previously unrecognized functional difference between PIEZO1 and PIEZO2. Moreover, by demonstrating that PKA only modulates PIEZO2 currents evoked by focal mechanical indentation of the cell, but not currents evoked by pressure-induced membrane stretch, we provide evidence suggesting that PIEZO2 is a polymodal mechanosensor that engages different protein domains for detecting different types of mechanical stimuli.

2023-07-20 | PXD041372 | Pride

Histone H3 K27M mediated Regulation of Cancer Cell Stemness and Differentiation in Diffuse Intrinsic Pontine Glioma (DIPG) [RNA-seq]

Project description:Diffuse intrinsic pontine glioma (DIPG) is a rare pediatric brain tumor with a median survival of 10-15 months. Histone H3 is mutated in 80% of DIPGs, dictating tumor location, onset, and outcome. Therapeutic resistance remains a major obstacle to preventing tumor recurrence and is in part driven by cancer stem cells (CSCs), which exhibit self-renewal properties and tumorigenic potential. In previous studies, we have identified these proliferative and tumorigenic features in aldehyde dehydrogenase positive (ALDH+) CSCs in H3K27M mutant DIPG. We hypothesize that ALDH-mediated cancer stemness and resistance may in part be driven by H3K27M. ALDH1A3 expression was reduced in CRISPR-edited DIPG cells (SU-DIPG-XIII) where the H3K27M mutation had been removed (H3K27M-KO). Furthermore, these gained differentiation characteristics and lost their neurosphere-forming potential. The parental (H3K27M) and H3K27M-KO cells were also subjected to ionizing radiation to identify genes responsible for radioresistance in histone-mutated DIPG radioresistance. Nascent transcriptomes were obtained from these cells using bromouridine labeling and capture followed by sequencing (Bru-seq).

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Dual role of Integrin alpha-6 in glioblastoma: supporting stemness in proneural stem-like cells while inducing radioresistance in mesenchymal stem-like cells

Project description:Therapeutic resistance after multimodal therapy is the most relevant cause of glioblastoma (GBM) recurrence. Extensive cellular heterogeneity, mainly driven by the presence of GBM stem-like cells (GSC), strongly correlates with patients’ prognosis and limited response to therapies. Defining the mechanisms which drive stemness and control responsiveness to therapy in a GSC-specific manner is therefore mandatory. Here we investigated the role of integrin a6 (ITGA6) in controlling stemness and resistance to radiotherapy in proneural and mesenchymal GSCs subtypes. Using cell sorting, gene silencing, RNA-Seq and in vitro assays, we verified that ITGA6 expression seems crucial for proliferation and stemness of proneural GSCs, while it appears not to be relevant in mesenchymal GSCs under basal conditions. However, when challenged with a fractionated protocol of radiation therapy, comparable to that employed in the clinical setting, mesenchymal GSCs turned out to be dependent on integrin a6 for survival. Specifically, GSCs with reduced levels of ITGA6 displayed a clear reduction of DNA-damage response and perturbation of cell cycle pathways. These data indicate that ITGA6 inhibition is able to overcome the radioresistance of mesenchymal GSCs, while it reduces proliferation and stemness in proneural GSCs. Therefore, integrin a6 controls crucial characteristics across GBM subtypes in GBM heterogeneous biology and thus may represent a promising target to improve patient outcomes

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Project description:The accumulation of acidic metabolic waste products within the tumor microenvironment profoundly inhibits effector functions of tumor-infiltrating lymphocytes (TILs). However, it is unclear whether extracellular-acidosis impacts T cell metabolic fitness and differentiation status. Here, we surprisingly found that prolonged acid exposure reprogrammed T cell intracellular metabolism and mitochondrial fitness, and preserved T cell stemness. Elevated extracellular-acidosis impaired methionine uptake and metabolism via downregulating SLC7A5, therefore altering H3K27me3 deposition at the promoters of crucial T cell stemness genes. These changes promoted the maintenance of a “stem-like memory” state and improved long-term in vivo persistence and anti-tumor efficacy. Our findings not only reveal the unexpected roles of extracellular-acidosis in the maintenance of stem-like properties of T cells, but also advance our understanding of the direct involvement of methionine metabolism in T cell stemness.

2023-01-17 | MTBLS6661 | MetaboLights

Expression analysis of miRNA involved in radioresistance of oral squamous cell carcinoma.

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2021-04-02 | GSE160122 | GEO

USP9X-mediated KDM4C deubiquitination promotes lung cancer radioresistance by epigenetically inducing TGFβ2 transcription

Project description:Radioresistance is regarded as the main barrier to effective radiotherapy in lung cancer. However, the underlying mechanisms of radioresistance remain elusive. Here, we show that lysine-specific demethylase 4C (KDM4C) is overexpressed and correlated with poor prognosis in lung cancer patients. We provide evidence that genetical or pharmacological inhibition of KDM4C impairs tumorigenesis and radioresistance in lung cancer in vitro and in vivo. Moreover, we uncover that KDM4C upregulates TGFβ2 expression by directly reducing H3K9me3 level at the TGFβ2 promoter and then activates TGF-β/Smad/ATM signaling to confer radioresistance in lung cancer. Using tandem affinity purification technology, we further identify deubiquitinase USP9X as a critical binding partner which deubiquitinates and stabilizes KDM4C. More importantly, depletion of USP9X impairs TGF-β/Smad signaling and radioresistance by destabilizing KDM4C in lung cancer cells. Thus, our findings demonstrate that USP9X-mediated KDM4C deubiquitination activates TGF-β/Smad signaling to promote radioresistance, suggesting that targeting KDM4C may be a promising radiosensitization strategy in the treatment of lung cancer.

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miRNAs were involved in the radioresistance of esophageal squamous cell carcinoma

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