1 INTRODUCTION
The brain, as the major organ of the central nervous system (CNS), controls and processes most of the body’s activities. Therefore, the most malignant brain tumors, namely, glioblastomas (GBMs) and brain metastases (BrMs), from extracranial primary tumors (such as lung, breast, melanoma, and colorectal cancers) are among the deadliest cancers with poor prognosis and short survival [1]. At present, an effective treatment option for patients with malignant brain tumors has long presented a challenge for oncologists.
Gliomas are one of the most prevalent tumors in the CNS with disproportionate mortality and morbidity among subtypes. The most commonly occurring types of gliomas are astrocytoma (WHO grade I - IV), oligodendroglioma (WHO grade II - III), and GBM [2, 3]. Glioma alterations, such as isocitrate dehydrogenase (IDH ) 1 and 2 mutations as well as 1p/19qcodeletion, generally occur in low grade gliomas (II or III) and provide superior prognostication compared to IDH wild-type tumors [4, 5]. Despite routine therapies, such as surgical resection, radiation, and chemotherapy, the outcomes of patients remain poor. The median survival rates of glioma patients are stubbornly low, varying from years (WHO grade II) to months (WHO grade IV) [6].
BrMs are 10 times more common than primary brain tumors with 10-30% incidence in adults, and they have an even lower survival rate that is typically measured in months [7, 8]. Fewer than 10% of all BrMs are found before the primary cancer is diagnosed. The determination of whether extracranial tumors develop BrMs relies mainly on cranial imaging [magnetic resonance imaging (MRI) or computed tomography (CT)], which has a severe time lag from diagnosis to treatment, causing the optimal therapeutic timeframe to be missed [9, 10]. In addition, although these two representative primary and secondary brain tumors exhibit markedly different modes of antigen presentation and tumor microenvironment [11], there is no effective molecular marker to assist in distinguishing these two types of brain tumors. The pathological diagnosis is confirmed by immunohistochemistry from tumor tissue obtained after surgery or a biopsy, which delays intervention and precise treatment selection. Consequently, accurate preoperative discrimination of BrM and glioma is critical for individualized therapeutic decision-making.
Markers found in the blood and tissue samples have been utilized for the diagnosis of the primary disease and to guide treatment. Recent studies applying immunohistochemistry, genome-wide transcriptomics, and single-cell transcriptomics to investigate BrMs and gliomas have had a profound impact on cancer biology [12-16]. Klemm et al. constructed a high-dimensional, multi-omics characterization of the brain tumor microenvironment, allowing elucidation of the disease- and cell type-specific expression patterns of gliomas and BrMs [17]. However, there are still challenges that hinder the transition of these findings into new effective therapies. Potential explanations for the disconnect between genomics-based studies and clinical trials include the lack of protein information and the poor correlation between protein and mRNA expression (0.54) [18, 19]. As the main carrier and executor of life activities, protein shows a more direct connection with the occurrence and development of diseases. Despite some transcriptomic studies, the precise proteomic composition of these two distinct human brain malignancies, especially BrMs, remains unclear. Thus, an integrated and in-depth proteomic analysis is required for the comprehensive understanding of these brain cancers.
Mass spectrometry (MS)-based proteomics is an integral part of cancer research, shedding light on the functional profile of the cancer cell. The present study demonstrated for the first time a systematic proteomic analysis of two typical malignant brain tumors, namely BrMs and gliomas. We generated and analyzed a comprehensive catalog of the disease type-specific protein expression patterns as a resource for the research community, and we also investigated their interrelationships.