Ron M.A. Heeren (Presenter)
Maastricht University, M4I
Bio: Prof. Dr. Ron M.A. Heeren obtained a PhD degree in technical physics in 1992 at the University of Amsterdam. In 2001 he was appointed professor at the chemistry faculty of Utrecht University lecturing on the physical aspects of biomolecular mass spectrometry. In the period 1995-2015 he has been developing new approaches towards high spatial resolution and high throughput molecular imaging mass spectrometry at FOM-AMOLF. In 2014 he was appointed as distinguished professor and Limburg Chair at the University of Maastricht and director of M4I, the Maastricht MultiModal Molecular Imaging institute and heads the division of imaging MS. His main research activities at M4I focus on the and realization of molecular imaging towards personalized medicine and intraoperative diagnostics.
Authorship: Ron M.A. Heeren, Shane R. Ellis, Anne Bruinen, Nina Ogrinc-Potocnik, Tiffany Porta and Joanna Cappell
M4I The Maastricht MultiModal Molecular imaging institute, Maastricht University.
| Short Abstract A multimodal approach for molecular imaging for clinical studies is trending the field of imaging mass spectrometry. More and more researchers realize that a single technology provides only a subset of the molecular information needed to obtain an in depth understanding of a clinical problem. Multimodal approaches enable the study of clinical samples at a variety of molecular and spatial scales. The molecular complexity on the genome, proteome and metabolome level all needs to be taken into account. The distribution of several hundreds of molecules on the surface of complex (biological) surfaces can be determined directly in complementary imaging MS experiment with MALDI and SIMS. This enables molecular pathway analysis as well as the analysis of the role and evolution of the different molecular signals during e.g. tumor development. |
Long Abstract
Introduction
A multimodal approach for molecular imaging for clinical studies is trending the field of imaging mass spectrometry. More and more researchers realize that a single technology provides only a subset of the molecular information needed to obtain an in depth understanding of a clinical problem. Multimodal approaches enable the study of clinical samples at a variety of molecular and spatial scales. The molecular complexity on the genome, proteome and metabolome level all needs to be taken into account. The distribution of several hundreds of molecules on the surface of complex (biological) surfaces can be determined directly in complementary imaging MS experiment with MALDI and SIMS. This enables molecular pathway analysis as well as the analysis of the role and evolution of the different molecular signals during e.g. tumor development.
Methods
State-of-the-art molecular imaging mass spectrometry has evolved to bridge the gap between different disciplines such as MRI, PET, fluorescence imaging and histology. The combination with tools from structural biology makes it possible to perform imaging experiments at length scales from cells to patients. Both secondary ion mass spectrometry and MALDI are performed to reveal molecular signals at the single cell level. Novel cluster beam approaches enable three dimensional analysis of single cells and organoids. High throughput, high resolution MALDI techniques offer three dimensional molecular data on the tissue level. In this lecture these methods will be employed in the study of high level tumor heterogeneity.
Results
Rapid MALDI-MSI instrumentation has been employed for the analysis of large numbers of tissues, 10 tumor xenografts (obtained from breast, lung and colon cancers) which were analysed in a single analysis with a 50 µm step size with DHB as the matrix. The resulting dataset contained >160,000 pixels and was acquired in ~90 minutes using 200 laser shots per raster position. Unsupervised tissue segmentation performed using SCiLS lab software(SCiLS Gmbh, Bremen, Germany) revealed distinct molecular profiles within the different tissue/tumor regions. In addition, high speed MALDI-MSI for the analysis of drugs of abuse in single human hairs will be presented. For example a single 4.8 cm long, longitudinally sections human hair could be imaged with 20µm pixel size in a matter of minutes.
Data demonstrating that such acquisition speeds enable the use of alternative matrices that previously could not be used in axial-ToF instruments for long imaging experiments due to their rapid evaporation in the high vacuum ion source. In particular we have used dithranol and 2,6-Dihydroxyacetophenone (DHA) for the imaging of lipids in both positive and negative mode sequentially from the same tissue section. Both matrices were found to yield excellent spectra in both polarities for a variety of lipids where dual polarity imaging provides highly complementary data for different lipid classes. Even for highly volatile DHA an entire sagittal mouse brain section could be imaged in both polarities in ~ 30 min before matrix evaporation significantly affected the acquisition.
Complementary data on a SIMS instrument was acquired on selected areas of these tumors without any sample preparation. Small metabolic signatures were employed to reveal different tumor cellular phenotypes employing cellular resolution. Regional classification was performed by PC-LDA and revealed different domains within the heterogeneous tumors.
Conclusion
We have demonstrated how new MS based chemical microscopes that target biomedical tissue analysis in various diseases as well as other chemically complex surfaces. In concert they elucidate the way in which local environments can influence molecular signaling pathways on various scales. The integration of this pathway information in a surgical setting is imminent, but innovations that push the boundaries of the technology and its application are still needed.
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