Proteomics Analysis of Brain Meningiomas in Pursuit of Novel Biomarkers of the Aggressive Behavior

Barkhoudarian, Garni; Whitelegge, Julian P.; Kelly, Daniel F.; Simonian, Margaret

doi:10.4172/jpb.1000389

Cited by 17 publications

(13 citation statements)

References 16 publications

(15 reference statements)

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“…Though limited in number, there have been recent studies that have uncovered newer insights into the way the tumors behave using several proteomics approaches ( 5 – 8 ). We earlier reported an elevation in the levels of AHNAK, Gelsolin, S100 family of proteins, and several other proteins like CKAP4 that were specific to particular grades of meningiomas ( 9 ).…”

Section: Introductionmentioning

confidence: 99%

Comprehending Meningioma Signaling Cascades Using Multipronged Proteomics Approaches & Targeted Validation of Potential Markers

et al. 2020

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Meningiomas are one of the most prevalent primary brain tumors. Our study aims to obtain mechanistic insights of meningioma pathobiology using mass spectrometry-based label-free quantitative proteome analysis to identifying druggable targets and perturbed pathways for therapeutic intervention. Label-free based proteomics study was done from peptide samples of 21 patients and 8 non-tumor controls which were followed up with Phosphoproteomics to identify the kinases and phosphorylated components of the perturbed pathways. In silico approaches revealed perturbations in extracellular matrix remodeling and associated cascades. To assess the extent of influence of Integrin and PI3K-Akt pathways, we used an Integrin Linked Kinase inhibitor on patient-derived meningioma cell line and performed a transcriptomic analysis of the components. Furthermore, we designed a Targeted proteomics assay which to the best of our knowledge for very first-time enables identification of peptides from 54 meningioma patients via SRM assay to validate the key proteins emerging from our study. This resulted in the identification of peptides from CLIC1, ES8L2, and AHNK many of which are receptors and kinases and are difficult to be characterized using conventional approaches. Furthermore, we were also able to monitor transitions for proteins like NEK9 and CKAP4 which have been reported to be associated with meningioma pathobiology. We believe, this study can aid in designing peptide-based validation assays for meningioma patients as well as IHC studies for clinical applications.

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Section: Introductionmentioning

confidence: 99%

Comprehending Meningioma Signaling Cascades Using Multipronged Proteomics Approaches & Targeted Validation of Potential Markers

et al. 2020

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“…Further studies have shown that knocking down AKAP12 in benign meningioma cells promotes proliferation, migration, and invasion, suggesting that AKAP12 is a central regulator of invasive meningioma progression ( 58 ). However, although studies have provided increasing evidence that post-translational modification is closely connected with cell-based functional characterization, which has a close connection with function and malignancy of the disease, phospho-proteomes are rarely studied in meningiomas ( 61 , 63 , 64 ).…”

Section: Proteomicsmentioning

confidence: 99%

Multi-Omics Analysis in Initiation and Progression of Meningiomas: From Pathogenesis to Diagnosis

2020

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Meningiomas are common intracranial tumors that can be cured by surgical resection in most cases. However, the most disconcerting is high-grade meningiomas, which frequently recur despite initial successful treatment, eventually conferring poor prognosis. Therefore, the early diagnosis and classification of meningioma is necessary for the subsequent intervention and an improved prognosis. A growing body of evidence demonstrates the potential of multi-omics study (including genomics, transcriptomics, epigenomics, proteomics) for meningioma diagnosis and mechanistic links to potential pathological mechanism. This thesis addresses a neglected aspect of recent advances in the field of meningiomas at multiple omics levels, highlighting that the integration of multi-omics can reveal the mechanism of meningiomas, which provides a timely and necessary scientific basis for the treatment of meningiomas.

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“…Few studies have investigated the proteome of benign meningiomas (21,22). Most of them lack clinical information and compare different grades.…”

Section: Introductionmentioning

confidence: 99%

Phosphoproteomic and Kinomic Signature of Clinically Aggressive Grade I (1.5) Meningiomas Reveals RB1 Signaling as a Novel Mediator and Biomarker

Parada

Osbun

Busald

et al. 2020

Clinical Cancer Research

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Purpose: Most World Health Organization (WHO) grade I meningiomas carry a favorable prognosis. Some become clinically aggressive with recurrence, invasion, and resistance to conventional therapies (grade 1.5; recurrent/progressive WHO grade I tumors requiring further treatment within 10 years). We aimed to identify biomarker signatures in grade 1.5 meningiomas where histopathology and genetic evaluation has fallen short. Experimental Design: Mass spectrometry (MS)-based phosphoproteomics and peptide chip array kinomics were used to compare grade I and 1.5 tumors. Ingenuity Pathway Analysis (IPA) identified alterations in signaling pathways with validation by Western blot analysis. The selected biomarker was evaluated in an independent cohort of 140 samples (79/140 genotyped for meningioma mutations) by tissue microarray and correlated with clinical variables. Results: The MS-based phosphoproteomics revealed differential Ser/Thr phosphorylation in 32 phosphopeptides. The kinomic profiling by peptide chip array identified 10 phosphopeptides, including a 360% increase in phosphorylation of RB1, in the 1.5 group. IPA of the combined datasets and Western blot validation revealed regulation of AKT and cell-cycle checkpoint cascades. RB1 hyperphosphorylation at the S780 site distinguished grade 1.5 meningiomas in an independent cohort of 140 samples and was associated with decreased progression/ recurrence-free survival. Mutations in NF2, TRAF7, SMO, KLF4, and AKT1 E17K did not predict RB1 S780 staining or progression in grade 1.5 meningiomas. Conclusions: RB1 S780 staining distinguishes grade 1.5 meningiomas, independent of histology, subtype, WHO grade, or genotype. This promising biomarker for risk stratification of histologically bland WHO grade I meningiomas provides insight into the pathways of oncogenesis driving these outlying clinically aggressive tumors.

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Proteomics Analysis of Brain Meningiomas in Pursuit of Novel Biomarkers of the Aggressive Behavior

Cited by 17 publications

References 16 publications

Comprehending Meningioma Signaling Cascades Using Multipronged Proteomics Approaches & Targeted Validation of Potential Markers

Comprehending Meningioma Signaling Cascades Using Multipronged Proteomics Approaches & Targeted Validation of Potential Markers

Multi-Omics Analysis in Initiation and Progression of Meningiomas: From Pathogenesis to Diagnosis

Phosphoproteomic and Kinomic Signature of Clinically Aggressive Grade I (1.5) Meningiomas Reveals RB1 Signaling as a Novel Mediator and Biomarker

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