Kinome and phosphoproteome of high-grade meningiomas reveal AKAP12 as a central regulator of aggressiveness and its possible role in progression

Abstract

There is a need to better understand meningioma oncogenesis for biomarker discovery and development of targeted therapies. Histological or genetic criteria do not accurately predict aggressiveness. Post-translational studies in meningioma progression are lacking. In the present work, we introduce a combination of mass spectrometry-based phosphoproteomics and peptide array kinomics to profile atypical and anaplastic (high-grade) meningiomas. In the discovery set of fresh-frozen tissue specimens (14), the A-kinase anchor protein 12 (AKAP12) protein was found downregulated across the grades. AKAP12 knockdown in benign meningioma cells SF4433 increases proliferation, cell cycle, migration, invasion, and confers an anaplastic profile. Differentially regulated pathways were characteristic of high-grade meningiomas. Low AKAP12 expression in a larger cohort of patients (75) characterized tumor invasiveness, recurrence, and progression, indicating its potential as a prognostic biomarker. These results demonstrate AKAP12 as a central regulator of meningioma aggressiveness with a possible role in progression.

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

“…Also, we validated targets like AHNAK, tumor-specific proteins like TPD52L2, TS101. Peptides corresponding to NEK9, SELENBP1 which were previously reported as a marker for aggressivity via two independent proteomics study were also optimized and monitored across the meningioma patient cohort ( 5 , 7 ). We further monitored the levels of PI3K-Akt and Integrin family members like EIF4G1 and CKAP4 ( Figure 6 , Supplementary Data 7 , 9 , and Supplementary Figures 5 , 6 ).…”

“…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 ).…”

Gravin-associated kinase signaling networks coordinate γ-tubulin organization at mitotic spindle poles

“…Other investigators have shown that Gravin loss is linked to defective mitoses in a variety of cancer cell lines (35,36). Recent phosphoproteomics studies further implicate this anchoring protein as a potential prognostic biomarker for high-grade meningiomas (35,36). Our discovery that Gravin-ablated cells display an enhanced pole-to-pole asymmetry of γ-tubulin provides additional clues into how protein scaffolds safeguard cell division events ( Figure 3F-K).…”

“…Our findings argue that Gravin-mediated signaling further contributes to this process. Other investigators have shown that Gravin loss is linked to defective mitoses in a variety of cancer cell lines (35,36). Recent phosphoproteomics studies further implicate this anchoring protein as a potential prognostic biomarker for high-grade meningiomas (35,36).…”

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

“…Proteomics can detect the differential expression of proteins in different grades or types of meningiomas ( Supplementary Table 3 ) ( 56 – 58 ). As early as 2006, the pure meningioma cell population was sequenced to indicate the differentially expressed proteins of each WHO grade meningioma.…”