The EGFR-TMEM167A-p53 Axis Defines the Aggressiveness of Gliomas

Segura-Collar, Berta; Gargini, Ricardo; Tovar-Ambel, Elena; Hernández‐SanMiguel, Esther; Epifano, Carolina; Castro, Ignacio Pérez de; Hernández-Laín, Aurelio; Casas‐Tintó, Sergio; Sánchez-Gómez, Pilar

doi:10.3390/cancers12010208

Cited by 14 publications

(12 citation statements)

References 33 publications

(56 reference statements)

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“…In CNV analysis, we found focal amplification peaks for oncogenes in the high PDIA5 group and focal deletion peaks for tumor suppressor genes. Several common somatic mutations in GBM including TP53, TTN, PTEN, and EGFR ( 52 ), were also present in the high PDIA5 group. These results suggest that high PDIA5 expression plays an important role in glioma infiltration.…”

Section: Discussionmentioning

confidence: 95%

PDIA5 is Correlated With Immune Infiltration and Predicts Poor Prognosis in Gliomas

Zhang

Dai

et al. 2021

Front. Immunol.

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Gliomas are the most common and lethal primary malignant tumor of the brain. Routine treatment including surgical resection, chemotherapy, and radiotherapy produced limited therapeutic effect, while immunotherapy targeting the glioma microenvironment has offered a novel therapeutic option. PDIA5 protein is the member of PDI family, which is highly expressed in glioma and participates in glioma progression. Based on large-scale bioinformatics analysis, we discovered that PDIA5 expression level is upregulated in aggressive gliomas, with high PDIA5 expression predicting poor clinical outcomes. We also observed positive correlation between PDIA5 and immune infiltrating cells, immune related pathways, inflammatory activities, and other immune checkpoint members. Patients with high PDIA5 high-expression benefited from immunotherapies. Additionally, immunohistochemistry revealed that PDIA5 and macrophage biomarker CD68 were upregulated in high-grade gliomas, and patients with low PDIA5 level experienced favorable outcomes among 33 glioma patients. Single cell RNA sequencing exhibited that PDIA5 was in high level presenting in neoplastic cells and macrophages. Cell transfection and co-culture of glioma cells and macrophages revealed that PDIA5 in tumor cells mediated macrophages exhausting. Altogether, our findings indicate that PDIA5 overexpression is associated with immune infiltration in gliomas, and may be a promising therapeutic target for glioma immunotherapy.

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Section: Discussionmentioning

confidence: 95%

PDIA5 is Correlated With Immune Infiltration and Predicts Poor Prognosis in Gliomas

Zhang

Dai

et al. 2021

Front. Immunol.

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“…Recent studies have suggested that tumors with immune-excluded phenotype also show infiltration of immune cells because the latter remain in the matrix around the tumor cell “nests” rather than penetrating the parenchyma of tumor cells ( 50 , 51 ). Moreover, we revealed a significant correlation between the subtypes and TMB, including several common somatic mutations (TP53, PTEN, and EGFR) in gliomas ( 52 ). mt-rRNA modification played an important part in formation of the “immune landscape” of the TME, which suggests that mt-rRNA modification may affect the therapeutic efficacy of ICBs.…”

Section: Discussionmentioning

confidence: 86%

Human Mitochondrial Ribosomal RNA Modification-Based Classification Contributes to Discriminate the Prognosis and Immunotherapy Response of Glioma Patients

Wang

et al. 2021

Front. Immunol.

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BackgroundEpigenetic regulations of the tumor microenvironment (TME) and immunotherapy have been investigated in recent years. Nevertheless, the potential value of mitochondrial ribosomal RNA (mt-rRNA) modification in regulation of the TME and immunotherapy remains unknown.MethodsWe comprehensively investigated the mt-rRNA-modification patterns in glioma patients based on nine regulators of mt-rRNA. Subsequently, these modification patterns were correlated systematically with immunologic characteristics and immunotherapy. An “mt-rRNA predictor” was constructed and validated in multiple publicly available cohorts to provide guidance for prognosis prediction and immunotherapy of glioma patients.ResultsTwo distinct patterns of mt-rRNA modification were determined based on the evidence that nine regulators of mt-rRNA correlated significantly with most clinicopathologic characteristics, immunomodulators, TME, immune-checkpoint blockers (ICBs), and prognosis. Patients with mt-rRNA subtype II presented significantly poorer overall survival/progression-free survival (OS/PFS), but higher tumor mutational burden (TMB), more somatic mutations, and copy number variation (CNV). These two mt-rRNA subtypes had distinct TME patterns and responses to ICB therapy. An mt-rRNA predictor was constructed and validated in four glioma cohorts. The subtype with high mt-rRNA score, characterized by increased TMB, infiltration of immune cells, and activation of immunity, suggested an immune-activated phenotype, and was also linked to greater sensitivity to immunotherapy using anti-programmed cell death protein 1 (PD-1) but resistance to temozolomide.ConclusionsRegulators of mt-rRNA modification have indispensable roles in the complexity and diversity of the TME and prognosis. This novel classification based on patterns of mt-rRNA modification could provide an effective prognostic predictor and guide more appropriate immunotherapy/chemotherapy strategies for glioma patients.

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“…Little is known about TMEM167A, but it has prognostic significance in lung cancer and glioma [ 57 , 58 ]. TMEM167A regulates vesicular trafficking, TNF and EGF signaling, and p53 transcription [ 29 ]. The compound silibinin has been shown to inhibit the TMEM family of receptors [ 57 , 58 ].…”

Section: Discussionmentioning

confidence: 99%

Targets for Renal Carcinoma Growth Control Identified by Screening FOXD1 Cell Proliferation Pathways

Bond

Sims‐Lucas

Oxburgh

2022

Cancers

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Clinical association studies suggest that FOXD1 is a determinant of patient outcome in clear cell renal cell carcinoma (ccRCC), and laboratory investigations have defined a role for this transcription factor in controlling the growth of tumors through regulation of the G2/M cell cycle transition. We hypothesized that the identification of pathways downstream of FOXD1 may define candidates for pharmacological modulation to suppress the G2/M transition in ccRCC. We developed an analysis pipeline that utilizes RNA sequencing, transcription factor binding site analysis, and phenotype validation to identify candidate effectors downstream from FOXD1. Compounds that modulate candidate pathways were tested for their ability to cause growth delay at G2/M. Three targets were identified: FOXM1, PME1, and TMEM167A, which were targeted by compounds FDI-6, AMZ-30, and silibinin, respectively. A 3D ccRCC tumor replica model was used to investigate the effects of these compounds on the growth of primary cells from five patients. While silibinin reduced 3D growth in a subset of tumor replicas, FDI-6 reduced growth in all. This study identifies tractable pathways to target G2/M transition and inhibit ccRCC growth, demonstrates the applicability of these strategies across patient tumor replicas, and provides a platform for individualized patient testing of compounds that inhibit tumor growth.

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The EGFR-TMEM167A-p53 Axis Defines the Aggressiveness of Gliomas

Cited by 14 publications

References 33 publications

PDIA5 is Correlated With Immune Infiltration and Predicts Poor Prognosis in Gliomas

PDIA5 is Correlated With Immune Infiltration and Predicts Poor Prognosis in Gliomas

Human Mitochondrial Ribosomal RNA Modification-Based Classification Contributes to Discriminate the Prognosis and Immunotherapy Response of Glioma Patients

Targets for Renal Carcinoma Growth Control Identified by Screening FOXD1 Cell Proliferation Pathways

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