Pharmacology & Toxicology

Glioma stem cell responses to therapeutic treatment are the main research focus of the Nilsson Laboratory
Glioblastoma multiforme (GBM), malignant primary brain tumors are characterized by low survival rate, high invasivity and resistance to apoptosis, necessitating a better understanding of the disease on a molecular level. The existence of malignant stem-like cells (glioma stem cells, GSCs) may explain a major source of tumor resistance. GSCs are largely resistant to therapies directed at differentiated cancer cells, including pharmacological treatment and radiation. Description of the pathological biology of GSCs is still in its infancy, with few original research papers published on this topic. Phenotypic characteristics of GSCs need to be correlated to the underlying cell signaling matrices that define their behavior. A powerful set of methods has been developed and applied to the study of GSC11 cell responses to perturbations in the STAT3/IL-6/HIF1α signaling network (J. Proteome Res., 2010, 9, 430-443). Similar studies need to be performed on other GSC cell lines in order to determine general mechanisms of therapeutic evasion as well as subsets of cells with clusters of resistance mechanisms. This work continues in collaboration with physician-scientists at The University of Texas M.D. Anderson Cancer Center in Houston, Texas and the Falk Center for Molecular Therapeutics in Evanston, Illinois.

Analysis of GSCs in cell culture will aid our understanding of their biology and is expected to yield the identity of novel targets for drug treatment. We are currently analyzing global protein and membrane protein expression in 37 GSC lines and will correlate those data with transcriptomic and glycomic datasets. Mass spectrometry-based detection and integrated analyses of tumor biomarkers are expected to rapidly enable typing and predict patient responses to therapeutic treatments. A second ongoing project is the study of differential proteomic responses of GSCs to treatment with an oncolytic virus. This promising therapy, developed by the team at M.D. Anderson, is entering phase II clinical trials. In further studies, we plan to define tumor responses to treatment in a system that more closely reflects in vivo conditions.

By use of refined analytical techniques that employ cutting-edge mass spectrometric instrumentation (matrix-assisted laser desorption/ionization time-of-flight imaging mass spectrometry, MALDI-IMS) that is unique to our region, we aim to determine the effect of treatment on molecular expression in in vitro cultured tissue slices (50-70 um) from neurosurgically removed patient tumors. This allows us to build molecular-histological maps to capture the glioma response in a condition that more accurately mirrors the tumor microenvironment in vivo, an important key to understanding clinical drug responses developing patient stratification schemes. We have also developed MALDI-IMS protocols for lipid imaging in collaborative studies of spinal cord injury and heavy ion-induced cancer.

Emmett, M.R., Kroes, R.A, Moskal, J.R., Conrad, C.A., Priebe, W., Laezza, F., Meyer-Baese, A., Nilsson, C.L. (2013) Integrative biological analysis for neuropsychopharmacology. Invited critical review for Neuropsychopharmacology, submitted.

Liu, H.; Lichti, C.F.; Mirfattah, B.; Frahm, J.; Nilsson, C.L. Optimization of tandem mass spectrometric data acquisition and data analysis of in vitro brominated peptides. Anal. Chem.2013, submitted.

Nilsson, C. L., Advances in quantitative phosphoproteomics. Anal. Chem. 2012.

Cardoso, R.; Love, R.; Nilsson, C.L.; Bergqvist, S.; Nowlin, D.; Yan, J.; Liu, K.K.-C.; Zhu, J.; Chen, P.; Deng, Y.-L.; Dyson, H.J; Greig, M.J.; Brooun, A. Identification of Cys255 in HIF-1α as a novel site for development of covalent inhibitors of HIF-1 α/ARNT PasB domain protei-protein interaction. Protein Sci. 2012,21(12), 1885-1896.

Nilsson, C.L. , Berven, F., Selheim, F., Liu, H., Moskal, J.R., Kroes, R.A., Sulman, E., conrad, C.A., Lang, F.F., Andren, P.E., Sariatgorji, M., Carlsohn, E., Lilua, H., Malm, J., Subramaniyam, D., Wag, X., Gozaales-Gonzales, M., Dasilva, N., Diez, P., Fuentes, M., Vegvan, A., Sjodin, K., Velinder, C., Laurell, T., Fehninger, T.E., Lindbert, H., Rezeli, M., Edula, G., Hober, S., Marko-Varga, G. Chromosome 19 annotations with disease speciation-A first report from the global research consortia. (2012) J. Proteome Res., 12(1) 135-150.

Dillon, R.; Nilsson, C. L.; Shi, S. D. H.; Lee, N. V.; Krastins, B.; Greig, M. J., Discovery of a Novel B-Raf Fusion Protein Related to c-Met Drug Resistance. J. Proteome Res. 2011, 10, (11), 5084-5094.

Kroes, R.A., Schmidt, M.E., He, H., Emmett, M.R., Nilsson, C.L., Moskal, J.R. (2010) Overexpression of ST6GalNAcV, a ganglioside-specific α2,6 sialyltransferase, inhibits glioma invasivity. Proc. Nat. Acad. Sci. USA, 107(28), 12646-51.

Zhang, H., McLoughlin, S., He, H., Nilsson, C.L., Loebbert, F., Dorwin, S., Pereda-Lopez, A., Xu, J., Solomon, L.R., Lake, M.R., Emmett, M.R., Marshall, A.G. (2009) Conformational effects of glycosylation of receptor of Advanced Glycation Endproducts (sRAGE) determined by mass-analyzed hydrogen/deuterium exchange for bacterial vs. mammalian expressed proteins. Biochemistry, submitted

He, H.; Nilsson, C. L.; Emmett, M. R.; Marshall, A. G.; Kroes, R. A.; Moskal, J. R.; Ji, Y.; Colman, H.; Priebe, W.; Lang, F. F.; Conrad, C. A., Glycomic and transcriptomic response of GSC11 glioblastoma stem cells to STAT3 phosphorylation inhibition and serum-induced differentiation. J Proteome Res 2010, 9, 2098-2108.

Nilsson, C.L., Dillon, R., Devakumar, A., Rogers, J.C., Krastins, B., Rosenblatt, M.M., Major, M., Kaboord, B.J., Sarracino, D., Rezai, T., Prakash, A., Lopez, M., Ji,Y., Priebe, W., Colman, H., Lang, F.F. and Conrad, C.A. (2010) Quantitative phosphoproteomic analysis of STAT3/IL-6/HIF1α signaling network: An initial study in GSC11 glioblastoma stem cells. J. Proteome Res., 9(1), 430-443.

He, H., Nilsson, C.L., Emmett, M. R., Wang, X., Marshall, A.G., Kroes, R.A., Moskal, J.R., Colman, H., Lang, F.F. and Conrad, C.A. (2010) Polar lipid remodeling and increased sulfatide expression are associated with the glioma therapeutic candidates, wild type p53 elevation and the topoisomerase-1 inhibitor, Irinotecan. Glycoconjugate J., 27 (1), 27-38.

Dillon, R.; Nilsson, C. L.; Shi, S. D. H.; Lee, N. V.; Krastins, B.; Greig, M. J., Discovery of a Novel B-Raf Fusion Protein Related to c-Met Drug Resistance. J. Proteome Res. 2011, 10, (11), 5084-5094.

He, H., Nilsson, C.L., Emmett, M. R., Marshall, A.G., Kroes, R.A., Moskal, J.R., Colman, H., Lang, F.F. and Conrad, C.A. (2010) Glycomic and transcriptomic response of GSC11 glioblastoma stem cells to STAT3 phosphorylation inhibition and serum-induced differentiation. J. Proteome Res., 9(5), 2098-2108.

Kroes, R. A.; Nilsson, C. L.; Emmett, M. R.; Moskal, J. R., Glycogene-based therapeutics for the treatment of malignant brain tumors: the kinase connection. Current Drug Targets 2011.

Nilsson, C. L.; Dillon, R.; Devakumar, A.; Rogers, J. C.; Krastins, B.; Rosenblatt, M. M.; Majo, M.; Kaboord, B. J.; Sarracino, D.; Rezai, T.; Prakash, A.; Lopez, M.; Ji, Y.; Priebe, W.; Colman, H.; Lang, F. F.; Conrad, C. A., Quantitative phosphoproteomic analysis of STAT3/IL-6/HIF1α signaling network: An initial study in GSC11 glioblastoma stem cells. J. Proteome Res. 2010, 9, (1), 430-443.

Puchades, M.; Nilsson, C. L.; Emmett, M. R.; Aldape, K. D.; Ji, Y.; Lang, F. F.; Liu, T. J.; Conrad, C. A., Proteomic investigation of glioblastoma cell lines treated with wild-type p53 and cytotoxic chemotherapy demonstrates an association between galectin-1 and p53 expression. J Proteome Res 2007, 6, 869-875.

Cardoso, R., Love, R., Nilsson, C.L., Bergqvist, S., Nowlin, D., Yan, J., Liu, K.K.-C., Zhu, J., Chen, P., Deng, Y.-L., Dyson, H.J., Greig, M.J. Brooun, A. Identification of Cys255 in HIF-1α as a novel site for development of covalent inhibitors of HIF-1 α/ARNT PasB domain protei-protein interaction.(2012) Protein Sci. 21(12), 1885-1896.