Mass spectrometry imaging (MSI) is a technology that simultaneously provides the spatial distribution of hundreds of biomolecules directly from tissue. Using essentially the same technique, and by slightly adapting sample preparation strategies, a wide pallet of molecular classes will be amenable for MSI analysis: small molecules (metabolites, pharmaceuticals), lipids, N-linked glycans, and proteins (intact, proteolytic fragments). The MSI analysis leads to minimal loss of histological information, and so the same tissue section may be histologically assessed and registered to the MSI datasets. In this manner the mass spectral signatures of specific cell types or histopathological entities, e.g. tumor cells, may be extracted from pathological tissue samples. This high cellular specificity is behind the increasing popularity of MSI in clinical research, and its proven ability to identify diagnostic and prognostic biomarkers.
The clinical application of MSI is highly multidisciplinary, requiring expertise in a number of fields. The research focus of LUMC has enabled a number of close, internal, working relationships to be formed that combine world leading groups, all under one roof.
Clinical application – Pathology, Surgery, Human Genetics
Multimodal imaging – Biomedical Image Analysis, Pathology, Image Guided Intervention
Molecular characterization – Center for Proteomics & Metabolomics
We have developed tools to measure the large numbers of samples required in clinical and preclinical investigations, to analyze multiple molecular classes, to efficiently analyze the large, high dimensionality datasets and to integrate the results with established biomedical imaging approaches. For example in a recent study of molecular changes following cortical spreading depression (the electrophysiological correlate of migraine with aura), performed in close collaboration with the migraine research group of Professor Arn van den Maagdenberg and the Biomedical Image Analysis group of Assoc. Professor Jouke Dijksta, we analyzed by MSI three molecular classes of 32 animals, registered all MSI datasets (through the tissue section’s histological image) to the reference mouse brain atlases Allen Brain Atlas, and then performed an anatomy-based analysis. In this manner we could efficiently identify disease related molecular changes specific to genotype and brain region (figure below).
The LUMC MSI group focuses on methodology development to address unmet clinical needs. Particular areas of clinical focus are the clonal evolution of tumors and their impact on patient diagnosis, prognosis and treatment response; tumor metabolism and microenvironment; neurological disorders (both episodic, such as migraine, and permanent).
The group is also at the forefront of efforts to better standardize and validate MSI methods for clinical research, so that these power, complementary molecular histological methods may be routinely applied. In collaboration with the group of Professor Axel Walch, at the Helmholtz Zentrum München,the group has published the first fully independent multicenter study and demonstrated that the biomarkers detected by MSI are robust, figure below.
The group is currently expanding on this work by standardizing and assessing the reproducibility of in-situ enzymatic reactions for the analysis of formalin-fixed, paraffin-embedded tissues in a multicenter collaboration with the M4I institute of Maastricht University, the Helmholtz Zentrum München, and the University of Dortmund.
Dr. Bram Heijs
Phone: +31 71 52 64154
Piga I, Heijs B, Nicolardi S, Giusti L, Marselli L, Marchetti P, Mazzoni MR, Lucacchini A, McDonnell LA. Ultra-high resolution MALDI-FTICR-MSI analysis of intact proteins in mouse and human pancreas tissue. Int J Mass Spectrom. 2017, doi: 10.1016/j.ijms.2017.11.001
Lou S, Balluff B, Cleven AH, Bovée JV, McDonnell LA. An experimental guideline for the analysis of histologically heterogeneous tumors by MALDI-TOF mass spectrometry imaging. Biochim Biophys Acta. 2016 Oct 8. pii: S1570-9639(16)30205-9. doi: 10.1016/j.bbapap.2016.09.020.
Holst S, Heijs B, de Haan N, van Zeijl RJ, Briaire-de Bruijn IH, van Pelt GW, Mehta AS, Angel PM, Mesker WE, Tollenaar RA, Drake RR, Bovée JV, McDonnell LA, Wuhrer M. Linkage-specific in situ sialic acid derivatization for N-glycan mass spectrometry imaging of formalin-fixed paraffin-embedded tissues. Anal Chem. 2016 Jun 7;88, 5904-5913. doi: 10.1021/acs.analchem.6b00819.
Heijs B, Abdelmoula WM, Lou S, Briaire-de Bruijn IH, Dijkstra J, Bovée JVMG, McDonnell LA. Histology-guided high-resolution matrix-assisted laser desorption/ionization mass spectrometry imaging. Anal Chem. 2015, 87, 11978-83. doi: 10.1021/acs.analchem.5b3610.
Balluff B, Frese CK, Maier SK, Schöne C, Kuster B, Schmitt M, Aubele M, Höfler H, Deelder AM, Heck AJR, Hogendoorn PCW, Morreau J, Altelaar AFM, Walch A, McDonnell LA. De novo discovery of phenotypic intra-tumor heterogeneity using imaging mass spectrometry. J Pathol. 2015, 235, 3-13.
Carreira RJ, Shyti R, Balluff B, Abdelmoula WM, van Heiningen SH, van Zeijl RJM, Dijkstra J, Ferrari MD, Tolner EA, McDonnell LA, van den Maagdenberg AMJM. Large-scale mass spectrometry imaging investigation of consequences of cortical spreading depression in a transgenic mouse model of migraine. J Am Soc Mass Spectrom. 2015.