Ferroptosis Activation Scoring Model Assists in Chemotherapeutic Agents’ Selection and Mediates Cross-Talk With Immunocytes in Malignant Glioblastoma

Wang, Zeyu; Dai, Ziyu; Zheng, Liancun; Xu, Binyuan; Zhang, Hao; Fan, Fan; Zhang, Xun; Liang, Xisong; Liu, Zhixiong; Yang, Kui; Cheng, Quan

doi:10.3389/fimmu.2021.747408

Cited by 24 publications

(20 citation statements)

References 57 publications

(69 reference statements)

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“…Sensitivity to A.770041, AMG.706, ABT.888, AP.24534, AS601245, AUY922, and AZ628 was higher in the low-risk group than the high-risk group, while sensitivity to axitinib, A.443654, AG.014699, AICAR, Akt inhibitor VIII, and ATRA was higher in the high-risk group than the low-risk group. These drugs are commonly used in the clinical treatment of gliomas, and our results support their therapeutic value in this context ( Djuzenova et al, 2012 ; Yuan et al, 2018 ; Wang et al, 2021c ; Milton et al, 2021 ). In addition, these findings suggest the prospect of targeting lncRNAs in therapy for patients with gliomas.…”

Section: Discussionsupporting

confidence: 81%

An m6A/m5C/m1A/m7G-Related Long Non-coding RNA Signature to Predict Prognosis and Immune Features of Glioma

Shao

Liu

et al. 2022

Front. Genet.

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Background: Gliomas are the most common and fatal malignant type of tumor of the central nervous system. RNA post-transcriptional modifications, as a frontier and hotspot in the field of epigenetics, have attracted increased attention in recent years. Among such modifications, methylation is most abundant, and encompasses N6-methyladenosine (m6A), 5-methylcytosine (m5C), N1 methyladenosine (m1A), and 7-methylguanosine (m7G) methylation.Methods: RNA-sequencing data from healthy tissue and low-grade glioma samples were downloaded from of The Cancer Genome Atlas database along with clinical information and mutation data from glioblastoma tumor samples. Forty-nine m6A/m5C/m1A/m7G-related genes were identified and an m6A/m5C/m1A/m7G-lncRNA signature of co-expressed long non-coding RNAs selected. Least absolute shrinkage and selection operator Cox regression analysis was used to identify 12 m6A/m5C/m1A/m7G-related lncRNAs associated with the prognostic characteristics of glioma and their correlation with immune function and drug sensitivity analyzed. Furthermore, the Chinese Glioma Genome Atlas dataset was used for model validation.Results: A total of 12 m6A/m5C/m1A/m7G-related genes (AL080276.2, AC092111.1, SOX21-AS1, DNAJC9-AS1, AC025171.1, AL356019.2, AC017104.1, AC099850.3, UNC5B-AS1, AC006064.2, AC010319.4, and AC016822.1) were used to construct a survival and prognosis model, which had good independent prediction ability for patients with glioma. Patients were divided into low and high m6A/m5C/m1A/m7G-LS groups, the latter of which had poor prognosis. In addition, the m6A/m5C/m1A/m7G-LS enabled improved interpretation of the results of enrichment analysis, as well as informing immunotherapy response and drug sensitivity of patients with glioma in different subgroups.Conclusion: In this study we constructed an m6A/m5C/m1A/m7G-LS and established a nomogram model, which can accurately predict the prognosis of patients with glioma and provides direction toward promising immunotherapy strategies for the future.

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Section: Discussionsupporting

confidence: 81%

An m6A/m5C/m1A/m7G-Related Long Non-coding RNA Signature to Predict Prognosis and Immune Features of Glioma

Shao

Liu

et al. 2022

Front. Genet.

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“…Increased expression of ferroptosis-promoting genes was detected in the GBM necrotic area (17). Ferroptosis-related genes were also linked to immunosuppressive microenvironment and poor prognosis of GBM (18)(19)(20)(21)(22). These studies suggested that ferroptosis is involved in the development of a necrotic core in GBM.…”

Section: Introductionmentioning

confidence: 99%

Temporal radiographic and histological study of necrosis development in a mouse glioblastoma model

et al. 2022

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Tumor necrosis is a poor prognostic marker in glioblastoma (GBM) and a variety of other solid cancers. Accumulating evidence supports that necrosis could facilitate tumor progression and resistance to therapeutics. GBM necrosis is typically first detected by magnetic resonance imaging (MRI), after prominent necrosis has already formed. Therefore, radiological appearances of early necrosis formation and the temporal-spatial development of necrosis alongside tumor progression remain poorly understood. This knowledge gap leads to a lack of reliable radiographic diagnostic/prognostic markers in early GBM progression to detect necrosis. Recently, we reported an orthotopic xenograft GBM murine model driven by hyperactivation of the Hippo pathway transcriptional coactivator with PDZ-binding motif (TAZ) which recapitulates the extent of GBM necrosis seen among patients. In this study, we utilized this model to perform a temporal radiographic and histological study of necrosis development. We observed tumor tissue actively undergoing necrosis first appears more brightly enhancing in the early stages of progression in comparison to the rest of the tumor tissue. Later stages of tumor progression lead to loss of enhancement and unenhancing signals in the necrotic central portion of tumors on T1-weighted post-contrast MRI. This central unenhancing portion coincides with the radiographic and clinical definition of necrosis among GBM patients. Moreover, as necrosis evolves, two relatively more contrast-enhancing rims are observed in relationship to the solid enhancing tumor surrounding the central necrosis in the later stages. The outer more prominently enhancing rim at the tumor border probably represents the infiltrating tumor edge, and the inner enhancing rim at the peri-necrotic region may represent locally infiltrating immune cells. The associated inflammation at the peri-necrotic region was further confirmed by immunohistochemical study of the temporal development of tumor necrosis. Neutrophils appear to be the predominant immune cell population in this region as necrosis evolves. This study shows central, brightly enhancing areas associated with inflammation in the tumor microenvironment may represent an early indication of necrosis development in GBM.

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“…Since ferroptosis was first defined, its function in cancer progression, chemotherapy, and immunotherapy has attracted great attention [ 51 ]. Increasing evidence indicates that iron-dependent programming death plays a vital role in shaping the cancer microenvironment and regulating antitumor immunity [ 52 – 55 ].…”

Section: Discussionmentioning

confidence: 99%

Transcriptional Patterns of Lower-Grade Glioma Patients with Distinct Ferroptosis Levels, Immunotherapy Response, and Temozolomide Sensitivity

Long

et al. 2022

Oxidative Medicine and Cellular Longevity

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Background. Many studies have defined a critical role for ferroptosis in cancer progression and therapy, but it is unclear how ferroptosis regulates tumor immunity or tumor microenvironment (TME). Methods. In this study, 24 ferroptosis-regulators were assessed by nonnegative matrix factorization (NMF) consensus clustering to identify ferroptosis patterns in lower-grade gliomas (LGGs). Cell-type Identification By Estimating Relative Subsets Of RNA Transcripts (CIBERSORT) method and single sample gene set enrichment analysis (ssGSEA) were used to quantify immune cell infiltrations. The PCA algorithm was used to develop the ferroptosis-related score (FRscore) to measure ferroptosis levels. Results. Two LGG subgroups named ferroptosis-related clusters 1 (FRC1) and 2 (FRC2), with distinct ferroptosis levels, immune infiltrations, and clinical outcomes were determined in 1,407 LGG samples. A well-designed scoring system was developed to evaluate the ferroptosis levels in LGG patients based on the FRSig gene profile and divided patients into low- and high-FRscore subgroups. Patients with low FRscores had lower ferroptosis levels and prolonged survival time and were expected to benefit from immune checkpoint blockade (ICB) therapy and showed higher sensitivity to TMZ chemotherapy. Findings also showed that the PI3K-AKT-mTOR pathway is activated by ferroptosis induction in SW1088 cells. Conclusions. This study highlights the critical role of ferroptosis in TME formation and shaping, and quantitatively assessing ferroptosis levels in individual tumors can help to define the intratumor microenvironment and formulate precise treatment strategies for LGG patients.

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Ferroptosis Activation Scoring Model Assists in Chemotherapeutic Agents’ Selection and Mediates Cross-Talk With Immunocytes in Malignant Glioblastoma

Cited by 24 publications

References 57 publications

An m6A/m5C/m1A/m7G-Related Long Non-coding RNA Signature to Predict Prognosis and Immune Features of Glioma

An m6A/m5C/m1A/m7G-Related Long Non-coding RNA Signature to Predict Prognosis and Immune Features of Glioma

Temporal radiographic and histological study of necrosis development in a mouse glioblastoma model

Transcriptional Patterns of Lower-Grade Glioma Patients with Distinct Ferroptosis Levels, Immunotherapy Response, and Temozolomide Sensitivity

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