Tumor cell-intrinsic Piezo2 drives radioresistance by impairing CD8+ T cell stemness maintenance
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE236339 | GEO | 2024/08/08
REPOSITORIES: GEO
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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
Project description:Tumor cell-intrinsic Piezo2 drives radioresistance by impairing CD8+ T cell stemness maintenance
| PRJNA990662 | ENA
Project description:Tumor cell-intrinsic Piezo2 drives radioresistance by impairing CD8+ T cell stemness maintenance
| PRJNA990673 | ENA
Project description:The clinical management of locally advanced oesophageal adenocarcinoma (OAC) commonly involves neoadjuvant chemoradiotherapy (CRT), but complete pathological response to CRT only occurs in 20-30% of patients, as radioresistance remains a major clinical challenge. In this study we used an established isogenic cell line model of radioresistant OAC to detect proteomic signatures of radioresistance in order to identify novel potential molecular and cellular targets of radioresistance in OAC. Intracellular proteins obtained from radiosensitive (OE33P) and radioresistant (OE33R) cells were subjected to LC-MS/MS analysis. We identified 5785 proteins of which 251 were significantly modulated in OE33R cells, when compared to OE33P. Gene ontology and pathway analysis of the significantly modulated proteins demonstrated altered metabolism in radioresistant cells accompanied by an inhibition of apoptosis in OE33R cells. In addition, radioresistant cells were predicted to have an activation of inflammatory and angiogenic pathways when compared to the radiosensitive cells. For the first time, we performed a comprehensive proteomic profiling of our established isogenic cell line model of radioresistant OAC, providing insights into the molecular and cellular pathways which regulates radioresistance in OAC, and we provided pathway specific signatures of radioresistance that will aid further studies on the development of targeted therapies and personalised approaches to radiotherapy, with the ultimate goal of improving response to radiotherapy in cancer patients.
2022-08-18 | PXD020303 | Pride
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.
2021-07-14 | GSE136404 | GEO
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
Project description:During the treatment of cutaneous melanoma, the presence of radioresistance compromised the therapeutic effects of radiotherapy. Yet, the mechanism of radioresistance in melanoma still remains unclear. Bioinformatic analysis of the transcriptomic sequencing showed PURPL was top up-regulated genes in response to ionizing radiation (IR) treatment in melanoma cells. Loss of PURPL notably repressed melanoma cell viability, colony formation, migration and invasiveness which potentiated PURPL’s role in radioresistance of melanoma. Further, loss-of- and gain-of-function analysis indicated that PURPL repressed IR-induced DNA damage and apoptosis. Mechanistically, RNA pulldown was performed and BID was identified as the interacting protein partner of PURPL. As the core gene of the mitochondrial apoptosis pathway, BID could be cleaved by Caspase-8 to generate tBID, which promotes the permeability of the mitochondrial membrane and the release of cytochrome c. IR treatment promotes the interaction between BID and Caspase-8 which was further strengthened by the loss of PURPL. The in vivo assays further verified the in vitro findings. Collectively, our study supports the pro-radioresistance role of PURPL in melanoma by inhibiting the interaction between BID and Caspase-8, which may provide a novel target for clinical radiotherapy.
2024-01-01 | GSE248024 | GEO
Project description:Purpose: Predominant causes of head and neck cancer recurrence after radiotherapy are rapid repopulation, hypoxia, fraction of cancer stem cells and intrinsic radioresistance. Currently, intrinsic radioresistance can only be assessed by ex-vivo colony assays. Besides being time-consuming, colony assays do not identify causes of intrinsic resistance. We aimed to identify a biomarker for intrinsic radioresistance to be used before start of treatment and to reveal biological processes that could be targeted to overcome intrinsic resistance. Experimental design: We analyzed both micro- and messenger RNA expression in a large panel of HNSCC cell lines. Expression was measured on both irradiated and unirradiated samples. Results were validated using modified cell lines and a series of laryngeal cancer patients. Results: MiRs, mRNAs and gene sets that correlated with resistance could be identified from expression data of unirradiated cells. The presence of epithelial to mesenchymal transition (EMT) and low expression of miRs involved in the inhibition of EMT were important radioresistance determinants. This finding was validated in two independent cell line pairs, in which the induction of EMT reduced radiosensitivity. Moreover, low expression of the most important miR (miR-203) was shown to correlate with local disease recurrence after radiotherapy in a series of laryngeal cancer patients. Conclusions: These findings indicate that EMT and low expression of EMT-inhibiting miRs, especially miR-203, measured in pre-treatment material, causes intrinsic radioresistance of HNSCC, which could enable identification and treatment modification of radioresistant tumors. Matched pairs of pre-treatment biopsies of 34 patients treated at The Netherlands Cancer Institute between 2002 and 2010. Patients with T2-3 laryngeal cancers, all treated with radiotherapy alone with a curative intent. The series was designed to be a matched cohort of 17 patients with local recurrences matched with 17 local cures. There were no significant differences between groups with and without local recurrence in age, gender, subsite, T-stage or treatment year.
2016-03-23 | E-GEOD-79493 | biostudies-arrayexpress
Project description:Background: Cancer cells inevitably develop resistance to radiation in lung cancer radiotherapy. However, the underlying mechanisms remain to be fully clarified. This study aimed to explore the roles and mechanisms of FGF1 intracellular binding protein (FIBP)?in lung cancer radioresistance. Methods: Expression levels of FIBP in human lung cancer and adjacent tissues were analyzed by immunohistochemical (IHC) staining. Cell growth and proliferation, EdU and CFSE assays, Neutral comet and clonogenic survival analysis as well as mouse xenograft model were performed to explore the functions of FIBP in vitro and in vivo. The underlying mechanisms were investigated by RNA sequencing, co-immunoprecipitation and dual luciferase reporter assays. Results: The expression levels of FIBP in lung cancer tissues were significantly upregulated compared with adjacent normal tissues and associated with worse overall survival. Functionally, we found that depletion of FIBP impairs lung cancer progression and radioresistance in vitro and in vivo. Mechanistically, we uncovered that FIBP interacts with STAT3 to enhance the transcriptional activity of STAT3, thereby inducing the expression of downstream target gene Eme1. Importantly, we also demonstrated that the biological effects of FIBP were partially dependent on Eme1 in lung cancer. Conclusions: These results reveal that FIBP modulates STAT3/Eme1 axis to drive lung cancer progression and radioresistance, indicating targeting FIBP may be a novel intervention strategy for lung cancer radiotherapy.
2022-06-06 | GSE196635 | GEO
Project description:Purpose: Predominant causes of head and neck cancer recurrence after radiotherapy are rapid repopulation, hypoxia, fraction of cancer stem cells and intrinsic radioresistance. Currently, intrinsic radioresistance can only be assessed by ex-vivo colony assays. Besides being time-consuming, colony assays do not identify causes of intrinsic resistance. We aimed to identify a biomarker for intrinsic radioresistance to be used before start of treatment and to reveal biological processes that could be targeted to overcome intrinsic resistance. Experimental design: We analyzed both micro- and messenger RNA expression in a large panel of HNSCC cell lines. Expression was measured on both irradiated and unirradiated samples. Results were validated using modified cell lines and a series of laryngeal cancer patients. Results: MiRs, mRNAs and gene sets that correlated with resistance could be identified from expression data of unirradiated cells. The presence of epithelial to mesenchymal transition (EMT) and low expression of miRs involved in the inhibition of EMT were important radioresistance determinants. This finding was validated in two independent cell line pairs, in which the induction of EMT reduced radiosensitivity. Moreover, low expression of the most important miR (miR-203) was shown to correlate with local disease recurrence after radiotherapy in a series of laryngeal cancer patients. Conclusions: These findings indicate that EMT and low expression of EMT-inhibiting miRs, especially miR-203, measured in pre-treatment material, causes intrinsic radioresistance of HNSCC, which could enable identification and treatment modification of radioresistant tumors.
2016-03-19 | GSE79370 | GEO