SPARCL1 – a new marker

Researchers at GIGA aim at identifying new protein markers of human glioma progression. For this purpose, they used glial tumors generated orthotopically with T98G and U373 human glioma cells in nude mice. This setup allowed also to discriminate the protein origin, namely, human (tumor) or mouse (host). Extracellular and membrane proteins were selectively purified using biotinylation followed by streptavidin affinity chromatography. Isolated proteins were digested and then identified and quantified employing 2D-nano-HPLC-MS/MS analysis. Following extensive validation, the results highlighted a repertoire of known and novel proteins in the context of human glioma. One of these was sparc-like protein 1 (SPRL1 [gene name: SPARCL1]).

SPRL1 overexpression in brain tumors of xenografted animals as well as in a large collection of human gliomas of different grades was confirmed by validation studies employing Western blot and immunohistochemistry.

Importantly, the expression pattern of SPRL1 correlated well with the progression stage of human glioma.

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COL6A1 – A new potential target

Researchers at GIGA have identified and characterized novel and accessible proteins using an innovative proteomic approach on six human glioblastomas. The corresponding data have been deposited in the PRIDE database identifier PXD001398.

Among several clusters of uniquely expressed proteins, they have highlighted collagen-VI-alpha-1 (COL6A1) as a highly expressed tumor biomarker with low levels in most normal tissues.

Immunohistochemical analysis of glioma samples from 61 patients demonstrated that COL6A1 is a significant and consistent feature of high-grade glioma.

Retrospective analysis of public gene-expression data sets from over 300 glioma patients demonstrated a significant correlation of poor patient outcome and high COL6A1 expression.

In a proof-of-concept study, they used chicken chorioallantoic membrane in vivo model to show that COL6A1 is a reachable target for IV-injected antibodies.

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CX30 – a new potential target

Researchers at GIGA and CHU analyzed the tumor suppressive effects of Cx30 in malignant astrocytic gliomas. They demonstrated the growth inhibitory potential in these tumors and dissected the involved signaling cascades. In addition, however, Cx30 protected human gliomas against radiation-induced DNA damage via a heat shock protein (HSP 90–dependent) translocation into the mitochondria favoring ATP production, DNA repair, and cell survival. In a clinical setting, it was shown that Cx30 expression adversely affected patient survival in 2 independent cohorts of radiation-treated glioblastoma patients.

These results demonstrate the central regulatory role of Cx30 in the biology of human gliomas. Acting as both a tumor growth suppressor and a radioprotective agent, this protein is a potential biomarker and an attractive target for specific therapeutic interventions against these tumors.

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HDAC7 – a new potential target

To date, the mutational status of EGFR and PTEN has been shown as relevant for favoring pro- or anti-tumor functions of STAT3 in human glioblastoma multiform (GBM).

Researchers at GIGA and CHU have screened genomic data from 154 patients and have identified a strong positive correlation between STAT3 and HDAC7 expression. In addition they have shown the existence of a subpopulation of patients overexpressing HDAC7 and STAT3 that has particularly poor clinical outcome.

Using in vitro and in vivo models, they demonstrated for the first time that silencing HDAC7 can reset the tumor suppressor activity of STAT3, independently of the EGFR/PTEN/TP53 background of the GBM.

This effect could help to overcome tumor heterogeneity and could subsequently provide a new rationale for the development of specific HDAC7 inhibitors in a clinical setting.

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Osteopontin – a New potential target

Researchers at GIGA have demonstrated the role of osteopontin in the tumorigenicity of glioblastoma cells and its importance in the maintenance of the stem characters.

Their recent studies focused on the potential role of osteopontin in the resistance of glioblastoma cells to radiotherapy and its implication in the initiation of Double Strand Breaks repair mechanism.

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CXCL12/CXCR4 signaling

Patients with glioblastoma multiform (GBM) have an overall median survival of 15 months. This catastrophic survival rate is the consequence of systematic relapses that could arise from remaining glioblastoma stem cells (GSCs) left behind after surgery.

Researchers at GIGA demonstrated that GSCs are able to escape the tumor mass and specifically colonize the adult subventricular zones (SVZs) after transplantation. This specific localization, away from the initial injection site, therefore represents a high-quality model of a clinical obstacle to therapy and relapses because GSCs notably retain the ability to form secondary tumors.

They questioned the role of the CXCL12/CXCR4 signaling in the GSC-specific invasion of the SVZs and demonstrated that both receptor and ligand are respectively expressed by different GBM cell populations and by the SVZ itself.

Using in vitro and in vivo models they revealed the significant role of the CXCL12/CXCR4 signaling in this original model of brain cancer invasion.

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Novel pharmaceutical formulations

Researchers at ULg have a broad expertise in the development of novel pharmaceutical formulations to improve the solubility and the bioavailability of compounds and to facilitate drug delivery to brain cells.

To test these new formulations, they have also developed a cellular blood brain barrier model using immortalized human cerebral microvascular endothelial cells.

For more information, click here.

Interested in these projects? Drop us an email [info@b2h.be]. We are looking forward collaborating with you!