Involvement of cell shape and lipid metabolism in glioblastoma resistance to temozolomide

Choo, Munki; Mai, Van-Hieu; Kim, Han Sun; Kim, Donghwa; Ku, Ja‐Lok; Lee, Sang Kook; Park, Chul‐Kee; An, Yong; Park, Sunghyouk

doi:10.1038/s41401-022-00984-6

Cited by 18 publications

(12 citation statements)

References 51 publications

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“…The result showed when intermediate methylation levels fell within 0.2 to 0.6, the PIM score correlated more with immune cell infiltration, stromal cell infiltration, tumour purity, mutation count, and aneuploidy percentage ( Figure 1a ), and showed greater correlation degrees with cell marker genes ( Figure 1b , Table S2), suggesting that DNA intermediate methylation (β-values ranges from 0.2 to 0.6) could be more indicative of the transcriptional diversity of cell marker genes. After comparing the methylation profiles of purified human immune cells with the tumour tissue (GBM sample from TCGA), we found the DNA methylation profiles of B cell, monocyte, macrophage, CD4 + T cell, natural killer cell, neutrophil, and two glioma cell lines, including U87 [ 52 ] and U251 [ 53 ] showed bimodal distributions. By contrast, more intermediate methylation sites were enriched in the tumour tissue ( Figure 1c ).…”

Section: Resultsmentioning

confidence: 99%

DNA methylation heterogeneity attributable to a complex tumor immune microenvironment prompts prognostic risk in glioma

Ma,

Pan,

Gan

et al. 2024

Epigenetics

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Gliomas are malignant tumours of the human nervous system with different World Health Organization (WHO) classifications, glioblastoma (GBM) with higher grade and are more malignant than lower-grade glioma (LGG). To dissect how the DNA methylation heterogeneity in gliomas is influenced by the complex cellular composition of the tumour immune microenvironment, we first compared the DNA methylation profiles of purified human immune cells and bulk glioma tissue, stratifying three tumour immune microenvironmental subtypes for GBM and LGG samples from The Cancer Genome Atlas (TCGA). We found that more intermediate methylation sites were enriched in glioma tumour tissues, and used the Proportion of sites with Intermediate Methylation (PIM) to compare intertumoral DNA methylation heterogeneity. A larger PIM score reflected stronger DNA methylation heterogeneity. Enhanced DNA methylation heterogeneity was associated with stronger immune cell infiltration, better survival rates, and slower tumour progression in glioma patients. We then created a Cell-type-associated DNA Methylation Heterogeneity Contribution (CMHC) score to explore the impact of different immune cell types on heterogeneous CpG site ( CpG ct ) in glioma tissues. We identified eight prognosis-related CpG ct to construct a risk score: the Cell-type-associated DNA Methylation Heterogeneity Risk (CMHR) score. CMHR was positively correlated with cytotoxic T-lymphocyte infiltration (CTL), and showed better predictive performance for IDH status (AUC = 0.96) and glioma histological phenotype (AUC = 0.81). Furthermore, DNA methylation alterations of eight CpG ct might be related to drug treatments of gliomas. In conclusion, we indicated that DNA methylation heterogeneity is associated with a complex tumour immune microenvironment, glioma phenotype, and patient’s prognosis.

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Section: Resultsmentioning

confidence: 99%

DNA methylation heterogeneity attributable to a complex tumor immune microenvironment prompts prognostic risk in glioma

Ma,

Pan,

Gan

et al. 2024

Epigenetics

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“… 25 Although the treatment of GBM has evolved over the years, most patients with GBM still have a very poor prognosis, with a 5-year relative survival rate of 5%. 26 TMZ is a common clinical chemotherapy for GBM, which can cross the blood–brain barrier and trigger tumor cell apoptosis; 27 however, resistance to TMZ develops quickly and frequently. In the current study, we found that ectopic expression of UBE2T decreases TMZ-induced GBM cell apoptosis, whereas UBE2T knockdown induces apoptosis.…”

Section: Discussionmentioning

confidence: 99%

UBE2T Promotes Temozolomide Resistance of Glioblastoma Through Regulating the Wnt/β-Catenin Signaling Pathway

Wang¹,

Gao²,

Wei³

et al. 2023

DDDT

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Purpose Patients with glioblastoma (GBM) have poor prognosis and limited therapeutic options, largely because of chemoresistance to temozolomide (TMZ) treatment. Ubiquitin conjugating enzyme E2 T (UBE2T) plays a key role in regulating the malignancy of various tumors, including GBM; however, its role in TMZ resistance of GBM has not been elucidated. The purpose of this study was to clarify the role of UBE2T in mediating TMZ resistance and investigate the specific underlying mechanism. Methods Western blotting was used to detect the protein levels of UBE2T and Wnt/β-catenin-related factors. CCK-8, flow cytometry, and colony formation assays were used to examine the effect of UBE2T on TMZ resistance. Wnt/β-catenin signaling pathway activation was inhibited using XAV-939, and a xenograft mouse model was generated to clarify the function of TMZ in vivo. Results UBE2T knockdown sensitized GBM cells to TMZ treatment, whereas UBE2T overexpression promoted TMZ resistance. The specific UBE2T inhibitor, M435-1279, increased the sensitivity of GBM cells to TMZ. Mechanistically, our results demonstrated that UBE2T induces β-catenin nuclear translocation and increases the protein levels of downstream molecules, including survivin and c-Myc. Inhibition of Wnt/β-catenin signaling using XAV-939 blocked TMZ resistance due to UBE2T overexpression in GBM cells. In addition, UBE2T was shown to facilitate TMZ resistance by inducing Wnt/β-catenin signaling pathway activation in a mouse xenograft model. Combined treatment with TMZ and UBE2T inhibitor achieved superior tumor growth suppression relative to TMZ treatment alone. Conclusion Our data reveal a novel role of UBE2T in mediating TMZ resistance of GBM cells via regulating Wnt/β-catenin signaling. These findings indicate that targeting UBE2T has promising potential to overcome TMZ resistance of GBM.

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“…For example, what is the molecular basis for longer event lifetimes in some cells versus changes to global shape fluctuation seen in others? While many specific hypotheses could be possible, such as RhoGEF activity 30, 31 , integrin expression level and repertoire 32, 33 , or metabolite availability and usage 34, 35 , the number of genomic differences between the different cell lines we inspected is too great to pinpoint any specific cause at this stage 36, 37 . However, the approach we have developed here will be well-suited to future studies aimed at identifying specific molecular drivers to each statistical axis we identify.…”

Section: Discussionmentioning

confidence: 99%

Comparative profiling of cellular gait on adhesive micropatterns defines statistical patterns of activity that underlie native and cancerous cell dynamics

Ahn,

Coyle

2023

Preprint

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Cell dynamics are powered by patterns of activity, but it is not straightforward to quantify these patterns or compare them across different environmental conditions or cell-types. Here we digitize the long-term shape fluctuations of metazoan cells grown on micropatterned fibronectin islands to define and extract statistical features of cell dynamics without the need for genetic modification or fluorescence imaging. These shape fluctuations generate single-cell morphological signals that can be decomposed into two major components: a continuous, slow-timescale meandering of morphology about an average steady-state shape; and short-lived "events" of rapid morphology change that sporadically occur throughout the timecourse. By developing statistical metrics for each of these components, we used thousands of hours of single-cell data to quantitatively define how each axis of cell dynamics was impacted by environmental conditions or cell-type. We found the size and spatial complexity of the micropattern island modulated the statistics of morphological events-lifetime, frequency, and orientation-but not its baseline shape fluctuations. Extending this approach to profile a panel of triple negative breast cancer cell-lines, we found that different cell-types could be distinguished from one another along specific and unique statistical axes of their behavior. Our results suggest that micropatterned substrates provide a generalizable method to build statistical profiles of cell dynamics to classify and compare emergent cell behaviors.

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Involvement of cell shape and lipid metabolism in glioblastoma resistance to temozolomide

Cited by 18 publications

References 51 publications

DNA methylation heterogeneity attributable to a complex tumor immune microenvironment prompts prognostic risk in glioma

DNA methylation heterogeneity attributable to a complex tumor immune microenvironment prompts prognostic risk in glioma

UBE2T Promotes Temozolomide Resistance of Glioblastoma Through Regulating the Wnt/β-Catenin Signaling Pathway

Comparative profiling of cellular gait on adhesive micropatterns defines statistical patterns of activity that underlie native and cancerous cell dynamics

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