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GENOMIC AND TRANSCRIPTIONAL ANALYSIS OF GLIOBLASTOMA MICROENVIRONMENTAL CELLULAR SUBSETS USING ANTIBODY MICROARRAYS

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Important molecular crosstalk in cancer

European researchers investigated the influence of the cancer microenvironment on tumour progression. Their findings could lead to targeted alternative treatments.

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Glioblastoma multiforme (GBM) is one of the most common, malignant and lethal primary brain tumours in adults. As in most human cancers, GBM consists of a mixture of cancer, immune, stromal and vascular cells. Accumulating evidence suggests that these non-cancerous components of the microenvironment play a critical role in tumour development and progression. The scope of the EU-funded CROSSTALK IN GBMS (Genomic and transcriptional analysis of glioblastoma microenvironmental cellular subsets using antibody microarrays) project was to perform genomic, transcriptomic and proteomic profiling of single cells and associate them with function. For this purpose, scientists applied the DEAL (DNA Encoded Antibody Library) technology to sort different cell phenotypes from heterogeneous GBM samples. Single cell analysis at the genomic, transcriptomic and proteomic levels followed by functional analysis allowed scientists to obtain significant insight into GBM. Great emphasis was given to tumour heterogeneity and pathway cross talk. Nearly 50 % of GBMs express a hyperactivated form of the epidermal growth factor receptor (EGFR) known as the variant III (EGFRvIII). Scientists studied if these GBMs would be sensitive to EGFR kinase inhibition or inhibition of the downstream effector, mechanistic Target of Rapamycin (mTOR). Resistance to EGFR inhibition was dealt with by a break in drug administration. This allowed cancer cells to rescue the remaining copies of EGFRvIII and regain their sensitivity. Additional factors such as hypoxia and pro-inflammatory cells contributed to EGFR drug resistance. Following molecular analysis of the pathways responsible, researchers proposed the use of combinatorial treatment against the mTOR and NF-kB pathways in GBM cells. As a means of evaluating the role of the microenvironment, they investigated the contribution of tumour-associated macrophages to tumour progression. M1 macrophages proved suppressive and induced apoptosis in GBM cells. The activities of the CROSSTALK IN GBMS project underscore the importance of the tumour microenvironment in cancer progression. Importantly it recognises the molecular cross-talk that could be exploited therapeutically for a better outcome.

Keywords

Microenvironment, glioblastoma multiforme, DEAL, EGFR, mTOR, NF-kb, macrophages

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