Integrated Meta-Omics Analysis Unveils the Pathways Modulating Tumorigenesis and Proliferation in High-Grade Meningioma.

Meningioma, a primary brain tumor, is commonly encountered and accounts for 39% of overall CNS tumors. Despite significant progress in clinical research, conventional surgical and clinical interventions remain the primary treatment options for meningioma. Several proteomics and transcriptomics studies have identified potential markers and altered biological pathways; however, comprehensive exploration and data integration can help to achieve an in-depth understanding of the altered pathobiology. This study applied integrated meta-analysis strategies to proteomic and transcriptomic datasets comprising 48 tissue samples, identifying around 1832 common genes/proteins to explore the underlying mechanism in high-grade meningioma tumorigenesis. The in silico pathway analysis indicated the roles of extracellular matrix organization (EMO) and integrin binding cascades in regulating the apoptosis, angiogenesis, and proliferation responsible for the pathobiology. Subsequently, the expression of pathway components was validated in an independent cohort of 32 fresh frozen tissue samples using multiple reaction monitoring (MRM), confirming their expression in high-grade meningioma. Furthermore, proteome-level changes in EMO and integrin cell surface interactions were investigated in a high-grade meningioma (IOMM-Lee) cell line by inhibiting integrin-linked kinase (ILK). Inhibition of ILK by administrating Cpd22 demonstrated an anti-proliferative effect, inducing apoptosis and downregulating proteins associated with proliferation and metastasis, which provides mechanistic insight into the disease pathophysiology.

A large-scale targeted proteomics of serum and tissue shows the utility of classifying high grade and low grade meningioma tumors.

BACKGROUND: Meningiomas are the most prevalent primary brain tumors. Due to their increasing burden on healthcare, meningiomas have become a pivot of translational research globally. Despite many studies in the field of discovery proteomics, the identification of grade-specific markers for meningioma is still a paradox and requires thorough investigation. The potential of the reported markers in different studies needs further verification in large and independent sample cohorts to identify the best set of markers with a better clinical perspective. METHODS: A total of 53 fresh frozen tumor tissue and 51 serum samples were acquired from meningioma patients respectively along with healthy controls, to validate the prospect of reported differentially expressed proteins and claimed markers of Meningioma mined from numerous manuscripts and knowledgebases. A small subset of Glioma/Glioblastoma samples were also included to investigate inter-tumor segregation. Furthermore, a simple Machine Learning (ML) based analysis was performed to evaluate the classification accuracy of the list of proteins. RESULTS: A list of 15 proteins from tissue and 12 proteins from serum were found to be the best segregator using a feature selection-based machine learning strategy with an accuracy of around 80% in predicting low grade (WHO grade I) and high grade (WHO grade II and WHO grade III) meningiomas. In addition, the discriminant analysis could also unveil the complexity of meningioma grading from a segregation pattern, which leads to the understanding of transition phases between the grades. CONCLUSIONS: The identified list of validated markers could play an instrumental role in the classification of meningioma as well as provide novel clinical perspectives in regard to prognosis and therapeutic targets.

Deciphering the Interregional and Interhemisphere Proteome of the Human Brain in the Context of the Human Proteome Project.

This study, which performs an extensive mass spectrometry-based analysis of 19 brain regions from both left and right hemispheres, presents the first draft of the human brain interhemispheric proteome. This high-resolution proteomics data provides comprehensive coverage of 3300 experimentally measured (nonhypothetical) proteins across multiple regions, allowing the characterization of protein-centric interhemispheric differences and synapse biology, and portrays the regional mapping of specific regions for brain disorder biomarkers. In the context of the Human Proteome Project (HPP), the interhemispheric proteome data reveal specific markers like chimerin 2 (CHN2) in the cerebellar vermis, olfactory marker protein (OMP) in the olfactory bulb, and ankyrin repeat domain 63 (ANKRD63) in basal ganglia, in line with regional brain transcriptomes mapped in the Human Protein Atlas (HPA). In addition, an in silico analysis pipeline was used to predict the structure and function of the uncharacterized uPE1 protein ANKRD63, and parallel reaction monitoring (PRM) was applied to validate its region-specific expression. Finally, we have built the Interhemispheric Brain Proteome Map (IBPM) Portal (www.brainprot.org) to stimulate the scientific community's interest in the brain molecular landscape and accelerate and support research in neuroproteomics. Data are available via ProteomeXchange with identifier PXD019936.

Comprehensive proteomic analysis reveals distinct functional modules associated with skull base and supratentorial meningiomas and perturbations in collagen pathway components.

Meningiomas are brain tumors that originate from the meninges and has been primarily classified into three grades by the current WHO guidelines. Although widely prevalent and can be managed by surgery there are instances when the tumors are located in difficult regions. This results in considerable challenges for complete surgical resection and further clinical management. While the genetic signature of the skull base tumors is now known to be different from the non-skull base tumors, there is a lack of information at the functional aspects of these tumors at the proteomic level. Thus, the current study thereby aims to obtain mechanistic insights between the two radiologically distinct groups of meningiomas, namely the skull base & supratentorial (non-skull base-NSB) regions. We have employed a comprehensive mass spectrometry-based label-free quantitative proteomic analysis in Skull base and supratentorial meningiomas. Further, we have used an Artificial Neural Networking employing a sparse Multilayer perceptron (MLP) architecture to predict protein concordance. A patient-derived spectral library has been employed for a novel peptide-level validation of proteins that are specific to the radiological regions using the SRM assay based targeted proteomics approach. The comprehensive proteomics enabled the identification of nearly 4000 proteins with high confidence (1%FDR ≥ 2 unique peptides) among which 170 proteins were differentially abundant in Skull base vs Supratentorial tumors (p-value ≤0.05). In silico analysis enabled mapping of the major alterations and hinted towards an overall perturbation of extracellular matrix and collagen biosynthesis components in the non-skull base meningiomas and a prominent perturbation of molecular trafficking in the skull base meningiomas. Therefore, this study has yielded novel insights into the functional association of the proteins that are differentially abundant in the two radiological subgroups. SIGNIFICANCE: In the current study, we have performed label-free proteomic analysis on fresh frozen tissue of 14 Supratentorial (NSB) and 7 Skull base meningiomas to assess perturbations in the global proteome, we have further employed an in-depth in silico analysis to map the pathways that have enabled functional mapping of the differentially abundant proteins in the Skull base and Supratentorial tumors. The findings from the above were also subjected to a machine learning-based neural networking to find out the proteins that have the most concordance of occurrence to determine the most influential proteins of the network. We further validated the differential abundance of identified protein markers in a larger patient cohort of Skull base and Supratentorial employing targeted proteomics approach to validate key protein candidates emerging from ours and other recent studies. The previous studies that have explored the skull base and convexity meningiomas have been able to reveal alterations in the genetic mutations in these tumor types. However, there are not many studies that have explored the functional aspects of these tumors, especially at the proteome level. We have attempted for the first time to map the functional modules associated with altered proteins in these tumors and have been able to identify that there is a possibility that the Skull base meningiomas to be considerably different from the Non-skull base (NSB) tumors in terms of the perturbed pathways. Our study employed global as well as targeted proteomics to examine the proteomic alterations in these two tumor groups. The study indicates that proteins that were more abundant in Skull base tumors were part of molecular transport components, non-skull base proteins majorly mapped to the components of extracellular matrix remodeling pathways. In conclusion, this study substantiates the distinction in the proteomic signatures in the skull base and supratentorial meningiomas paving way for further investigation of the identified markers for determining if some of these proteins can be used for therapeutic interventions for cases that pose considerable challenges for complete resection.

Correction: MTSS1 and SCAMP1 cooperate to prevent invasion in breast cancer.

The financial support for this Article was not fully acknowledged. The Acknowledgements should have included the following: "This study was supported by the European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement no 641549, Immutrain." The PDF and HTML versions of the paper have been modified accordingly.

An Artificial Neural Network Integrated Pipeline for Biomarker Discovery Using Alzheimer's Disease as a Case Study.

The field of machine learning has allowed researchers to generate and analyse vast amounts of data using a wide variety of methodologies. Artificial Neural Networks (ANN) are some of the most commonly used statistical models and have been successful in biomarker discovery studies in multiple disease types. This review seeks to explore and evaluate an integrated ANN pipeline for biomarker discovery and validation in Alzheimer's disease, the most common form of dementia worldwide with no proven cause and no available cure. The proposed pipeline consists of analysing public data with a categorical and continuous stepwise algorithm and further examination through network inference to predict gene interactions. This methodology can reliably generate novel markers and further examine known ones and can be used to guide future research in Alzheimer's disease.

MTSS1 and SCAMP1 cooperate to prevent invasion in breast cancer.

Cell-cell adhesions constitute the structural "glue" that retains cells together and contributes to tissue organisation and physiological function. The integrity of these structures is regulated by extracellular and intracellular signals and pathways that act on the functional units of cell adhesion such as the cell adhesion molecules/adhesion receptors, the extracellular matrix (ECM) proteins and the cytoplasmic plaque/peripheral membrane proteins. In advanced cancer, these regulatory pathways are dysregulated and lead to cell-cell adhesion disassembly, increased invasion and metastasis. The Metastasis suppressor protein 1 (MTSS1) plays a key role in the maintenance of cell-cell adhesions and its loss correlates with tumour progression in a variety of cancers. However, the mechanisms that regulate its function are not well-known. Using a system biology approach, we unravelled potential interacting partners of MTSS1. We found that the secretory carrier-associated membrane protein 1 (SCAMP1), a molecule involved in post-Golgi recycling pathways and in endosome cell membrane recycling, enhances Mtss1 anti-invasive function in HER2+/ER-/PR- breast cancer, by promoting its protein trafficking leading to elevated levels of RAC1-GTP and increased cell-cell adhesions. This was clinically tested in HER2 breast cancer tissue and shown that loss of MTSS1 and SCAMP1 correlates with reduced disease-specific survival. In summary, we provide evidence of the cooperative roles of MTSS1 and SCAMP1 in preventing HER2+/ER-/PR- breast cancer invasion and we show that the loss of Mtss1 and Scamp1 results in a more aggressive cancer cell phenotype.

Discovery and application of immune biomarkers for hematological malignancies.

INTRODUCTION: Hematological malignancies originate and progress in primary and secondary lymphoid organs, where they establish a uniquely immune-suppressive tumour microenvironment. Although high-throughput transcriptomic and proteomic approaches are being employed to interrogate immune surveillance and escape mechanisms in patients with solid tumours, and to identify actionable targets for immunotherapy, our knowledge of the immunological landscape of hematological malignancies, as well as our understanding of the molecular circuits that underpin the establishment of immune tolerance, is not comprehensive. Areas covered: This article will discuss how multiplexed immunohistochemistry, flow cytometry/mass cytometry, proteomic and genomic techniques can be used to dynamically capture the complexity of tumour-immune interactions. Moreover, the analysis of multi-dimensional, clinically annotated data sets obtained from public repositories such as Array Express, TCGA and GEO is crucial to identify immune biomarkers, to inform the rational design of immune therapies and to predict clinical benefit in individual patients. We will also highlight how artificial neural network models and alternative methodologies integrating other algorithms can support the identification of key molecular drivers of immune dysfunction. Expert commentary: High-dimensional technologies have the potential to enhance our understanding of immune-cancer interactions and will support clinical decision making and the prediction of therapeutic benefit from immune-based interventions.