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Glioblastoma is an aggressive form of brain cancer with well-established patterns of intra-tumoral heterogeneity implicated in treatment resistance and progression. While regional and single cell transcriptomic variations of glioblastoma have been recently resolved, downstream phenotype-level proteomic programs have yet to be assigned across glioblastoma’s hallmark histomorphologic niches. Here, we leverage mass spectrometry to spatially align abundance levels of 4,794 proteins to distinct histologic patterns across 20 patients and propose diverse molecular programs operational within these regional tumor compartments. Using machine learning, we overlay concordant transcriptional information, and define two distinct proteogenomic programs, MYC- and KRAS-axis hereon, that cooperate with hypoxia to produce a tri-dimensional model of intra-tumoral heterogeneity. Moreover, we highlight differential drug sensitivities and relative chemoresistance in glioblastoma cell lines with enhanced KRAS programs. Importantly, these pharmacological differences are less pronounced in transcriptional glioblastoma subgroups suggesting that this model may provide insights for targeting heterogeneity and overcoming therapy resistance. Gioblastoma tumours consist of different niches defined by histology. Here, the authors use proteomics and machine learning to assign protein expression programs to these niches, and reveal that KRAS and hypoxia are associated with drug resistance.

Although treatment outcomes of glioblastoma, the most malignant central nervous system (CNS) tumor, has improved in the past decades, it is still incurable, and survival has only slightly improved. Advances in molecular biology and genetics have completely transformed our understanding of glioblastoma. Multiple classifications and different diagnostic methods were made according to novel molecular markers. Discovering tumor heterogeneity only partially explains the ineffectiveness of current anti-proliferative therapies. Dynamic heterogeneity secures resistance to combined oncotherapy. As tumor growth proceeds, new therapy-resistant sub clones emerge. Liquid biopsy is a new and promising diagnostic tool that can step up with the dynamic genetic change. Getting a ’real-time’ picture of a specific tumor, anti-invasion and multi-target treatment can be designed. During invasion to the peri-tumoral brain tissue, glioma cells interact with the extracellular matrix components. The expressional levels of these matrix molecules give a characteristic pattern, the invasion spectrum, which possess vast diagnostical, predictive and prognostic information. It is a huge leap forward combating tumor heterogeneity and searching for novel therapies. Using the invasion spectrum of a tumor sample is a novel tool to distinguish between histological subtypes, specifying the tumor grades or different prognostic groups. Moreover, new therapeutic methods and their combinations are under trial. These are crucial steps towards personalized oncotherapy.

The extent of tumor removal determines the effectiveness of postoperative oncotherapy. This is especially true for primary brain tumors, where peritumoral invasion usually makes radical resection impossible. The aim of the study was to determinate the specific expression pattern of invasion related molecules of different intracranial tumors and to identify molecules that are principally responsible for the peritumoral invasiveness of grade II astrocytoma mRNA expression of 26 extracellular matrix (ECM) molecules was determined in tissue samples from grade II astrocytoma, schwannoma, intracerebral metastases of non-small cell lung cancer and normal brain. Immunohistochemical staining for brevican, neurocan, tenascin-C and versican was also performed for each tumor group. Comparing astrocytoma to metastasis, schwannoma and normal brain; and metastasis and schwannoma to normal brain, 22, 17, 20, 21, and 19 molecules, respectively, were found to be significantly overexpressed at the mRNA level. Cluster analysis of mRNA expression showed a specific gene expression pattern for each histological group. Four molecules of 26 were found to be associated to astrocytoma. Immunohistochemical staining confirmed the results of the mRNA analysis at the protein level. Tumors of different origin have a specific invasive phenotype that can evidently determinate on gene expression level. This characteristic expression pattern of the invasion-related molecules might help to screen exact targets for anti-invasion drugs. In case of low-grade astrocytoma. brevican, neurocan, tenascin-C and versican were found to correlate principally with the invasive phenotype of low-grade astrocytoma, thus these molecules can potentially serve as targets for anti-invasion therapy in the future.

Peritumoral infiltration is characteristic of astrocytomas even in low-grade tumors. Tumor cells migrate to neighbouring tissue and cause recurrence. The extracellular matrix (ECM) plays a role in tumor invasion; expression levels of its components’ have been linked to tumor invasion. This study determines the mRNA and protein expression of 20 invasion-related ECM components by examining non-tumor brain; grade I-II-III astrocytoma and glioblastoma samples. Expression levels were measured by QRT-PCR and mass-spectroscopy. The connection between the expression pattern and tumor grade is statistically analyzed. During the analysis of data, key molecules (brevican, cadherin-12, fibronectin and integrin-β1) correlating the most with tumor grade were selected. While the mRNA level of brevican, ErbB2, fibronectin, integrin-β1 and versican discriminates low-grade from high-grade gliomas, of proteins RHAMM, integrin-α1 and MMP2 seems important. The expression pattern was found to be distinctive for tumor grade, as statistical classifiers are capable of identifying an unknown sample’s grade using them. Furthermore, normal brain and glioma expression patterns, along with low-grade astrocytoma and glioblastoma samples, differ the most. Determining the invasion-related molecules’ expression profile provides extra information regarding the tumor’s clinical behavior. Additionally, identifying molecules playing a key role in glioma invasion could uncover potential therapeutic targets in the future.

•Gene and protein levels of ECM molecules in human brain samples were examined.•Differences in the peritumoral and normal tissues were revealed.•We could identify molecules that may affect the peritumoral invasion processes.•ECM of peri-glioblastoma does not react definitely to the spreading of the tumour.•Peri-metastatic ECM changes can probably decrease tumour infiltration. The effectiveness of therapy of intracerebral neoplasms is mainly influenced by the invasive behaviour of the tumour. The peritumoral invasion depends on the interaction between the tumour cells and the extracellular matrix (ECM) of the surrounding brain. The invading tumour cells induce change in the activity of proteases, synthases and expression of ECM-components. These alterations in the peritumoral ECM are in connection to the highly different invasiveness of gliomas and metastatic brain tumours. To understand the fairly modified invasive potential of anaplastic intracerebral tumours of different origin, the effect of tumour on the peritumoral ECM and alterations of invasion related ECM components in the peritumoral brain were evaluated. For this reason the mRNA expression of 19 invasion-related molecules by quantitative reverse transcriptase polymerase chain reaction was determined in normal brain tissue (Norm), in the peritumoral brain tissue of glioblastoma (peri-GBM) and of intracerebral adenocarcinoma metastasis (peri-Met). To evaluate the translational expression of the investigated molecules protein levels were determined by targeted proteomic methods. Establishing the invasion pattern of the investigated tissue samples 8 molecules showed concordant difference at mRNA and protein levels in the peri-GBM and peri-Met, 11 molecules in the peri-Met and normal brain and 12 in the peri-GBM and normal brain comparison. Our results bring some ECM molecules into focus that probably play key role in arresting tumour cell invasion around the metastatic tumour, and also in the lack of impeding tumour cell migration in case of glioblastoma.

Glioblastoma (GBM) is the most common primary brain tumor in adults with inevitable recurrence after oncotherapy. The insufficient effect of “gold standard” temozolomide-based concomitant radiochemotherapy may be due to the inability to prevent tumor cell invasion. Peritumoral infiltration depends mainly on the interaction between extracellular matrix (ECM) components and cell membrane receptors. Changes in invasive behaviour after oncotherapy can be evaluated at the molecular level by determining the RNA expression and protein levels of the invasion-related ECM components. The expression of nineteen ECM molecules was determined at both RNA and protein levels in thirty-one GBM samples. Fifteen GBM samples originated from the first surgical procedure on patients before oncotherapy, and sixteen GBM samples were collected at the second surgery due to local recurrence after concomitant chemoirradiation. RNA expressions were measured with qRT-PCR, and protein levels were determined by quantitative analysis of Western blots. Only MMP-9 RNA transcript level was reduced ( p  < 0.05) whereas at protein level, eight molecules showed changes concordant with RNA expression with significant decrease in brevican only. The results suggest that concomitant radiochemotherapy does not have sufficient impact on the expression of invasion-related ECM components of glioblastoma, oncotherapy does not significantly affect its invasive behavior. To avoid the spread of tumors into the brain parenchyma, supplementation of antiproliferative treatment with anti-invasive agents may be worth consideration in oncotherapy for glioblastoma.

A glioblasztóma multiforme (GBM) a leggyakoribb felnőttkori elsődleges agydaganat, és egyike a legrosszabb prognózisú betegségeknek. Törvényszerű kiújulásának egyik feltételezett oka a tumor kifejezett infiltratív jellege. A környezetet beszűrő tumorsejtek változást hoznak létre a peritumorális mátrix komponensek expressziójában. A GBM kezelésében a standard konkuráló kemoirradiáció hónapokat növelt ugyan az átlagos és a progressziómentes túlélésen, de átütő sikert nem ér el. A temozolomid-ra épülő kemoterápia ineffektivitásának egyik feltételezett oka, hogy az antiproliferatív kezelés nem hat lényegesen a daganatsejtek infiltrációjára. Az invazivitás okozta peritumorális szöveti változásra és az invazivitás onkoterápiára bekövetkező esetleges megváltozására molekuláris szinten a peritumorális agyszövetben és a daganatban lévő extracelluláris mátrix alkotóelemeinek expressziós szintjében bekövetkezett változások utalhatnak. Erre fókuszálva jelen munkánkban 20 db invázióhoz köthető molekula mRNS és fehérje szintjét határoztuk meg, azRNS szinteket Q-PCR, a fehérje szinteket pedig kvantitatív proteomikai analízis segítségével. A molekulákat tumormentes agyszövetben (Norm/9db), glioblasztóma (PeriGBM/9db) és intracerebrális adenokarcinóma metasztázis (Peri-Met/9db) peritumorális agyszövetében valamint konkuráló kemoirradiáció előtti (kezeletlen/15db) és utáni (kezelt/16db) glioblasztóma mintákban vizsgáltuk. Létrehozva a vizsgált szövetek inváziós mintázatát eredményeink több ECM molekulát is kiemelnek, amelyek feltehetően szerepet játszanak a metasztázisok inváziójának megakadályozásában és a glioblasztóma sejtek migrációjának gátlási képtelenségében: CD168, Fibronektin, MMP-9, Tenaszcin-C, Tenaszcin-R. Emellett feltételezhető, hogy a kemoirradiationak nincs lényeges hatása a glioblasztómák extracelluláris mátrixának összetételére és ezáltal nem hat érdemlegesen a daganat infiltratív jellegére. Véleményünk szerint az antiproliferatív ágensek antiinvazív készítményekkel való kiegészítése a GBM kezelésében megfontolást érdemel.

Compared to rodents, inhibitory interneurons in the human neocortex exhibit high input excitability because of reduced passive ion leakage across their extracellular membrane. However, the regulation of intrinsic excitability by voltage-gated ion channels activated over a wide range of membrane potentials in human interneurons remains poorly understood. We performed whole-cell patch-clamp microelectrode recordings in mouse and human neocortical slices obtained from surgically resected non-pathological brain tissue finding that Kir channels control the electrical resistance of parvalbumin (Pvalb) neurons in an identical manner in the human and mouse. Molecular analyses revealed predominantly Kir3.1 and Kir3.2 channels in Pvalb neurons in both species. Using whole-cell recordings from synaptically connected neuron pairs and a computational model, we demonstrated that physiological Kir activation inhibits human Pvalb interneurons during postsynaptic potentials evoked by presynaptic neurogliaform cells. The similarity of Kir-mediated inhibition across species suggests that it is an archetypal property of Pvalb neurons.

The mammalian brain exhibits notable interspecies variation. Microanatomical and molecular differences in homologous neurons, those with similar locations and developmental origins across species, are best characterized in the neocortical mantle, the center of complex brain functions; however, the purpose of these differences remains unclear. We performed whole-cell microelectrode recordings along with microanatomical and molecular analyses of human fast-spiking parvalbumin (pvalb)-expressing interneurons in neocortical tissue resected during brain surgery, comparing them with similar data obtained from the mouse neocortex. The action potential (AP) firing threshold was lower in human neurons than in mouse neurons. This was due to a deficiency in low-voltage-activated inhibitory Kv1.1 and Kv1.2 potassium channels in the axon initial segment (AIS), a specialized axonal region that determines AP threshold and initiation, in human cells. In contrast, Kv1 ion channels were prominent in mouse neurons. The AIS was also elongated in humans. Computational simulations of fast-spiking interneurons revealed that the human-type AIS lowers the AP threshold and shortens the time lag for AP initiation. We found that the low membrane AP firing threshold in pvalb neurons is closely linked to slow membrane potential kinetics in the soma. Thus, the human AIS supports fast in-fast out circuit function in human pvalb neurons, compensating for electrically slow somatic membrane responses. When formulating therapeutic strategies that involve fast- spiking neurons, it is crucial to take into account the molecular and functional species differences. Fast-spiking neurons in the human neocortex feature structural and molecular specializations in the axon initial segment that lower firing thresholds and minimize input- output delay.

The mammalian brain exhibits various interspecies differences. Microanatomical and molecular differences in homologous neurons between species are best characterized in the neocortical mantle, but the purpose of these differences remains poorly understood. We performed whole-cell microelectrode recordings and microanatomical and molecular analyses of human fast-spiking parvalbumin (pvalb)-expressing interneurons in neocortical tissue resected during brain surgery. Fast-spiking interneurons exhibited a lower action potential (AP) firing threshold in humans than in mice. Compared with mouse neurons, human neurons displayed an elongated axon initial segment (AIS), and the human AIS was deficient in low-voltage activated inhibitory Kv1 potassium channels. Contrarily, Kv1 ion channels were prominent in mouse neurons. Computational fast-spiking interneuron model simulations revealed that human-type AIS lowers the AP threshold and shortens the time lag for AP generation. Thus, human AIS supports fast in–fast out electrical circuit function in human pvalb neurons, which have electrically slow membrane potential kinetics in somata. Fast-spiking neurons in the human neocortex have structural and molecular adaptations in the axon to shorten IN-OUT delay