Research Unit Analytical Pathology

Understanding tumor heterogeneity presents one of the most important tasks in cancer research towards improving both diagnosis and treatment of patients. Heterogeneity of tumors contributes to treatment failure and disease recurrence, whereas the interaction between tumor cells and the associated stroma poses novel therapeutic opportunities. Intratumoral heterogeneity refers to the fact that cells within a tumor mass can be highly diverse due to an evolving process in cancer development driven by the stepwise accumulation of molecular changes and clonal selection, while intertumoral heterogeneity describes molecular alterations in several (metastatic) tumors present within or between patients. In malignant cells alteration in molecular features and clonal selection constantly takes place and provides either a selective advantage in function such as proliferation and survival, proceed neutral without any effects, or has negative cell damaging effects. Thereby, the fitness of a neoplastic cell is affected by the interactions with itself and other cells in its microenvironment competing with one another for the available resources. Tumor heterogeneity has mainly been described at a genetic, chromosomal, or transcriptional level. The approaches used to analyze tumor heterogeneity are mostly targeted either focusing on the distribution of a single molecule in tissues such as proteins by using immunohistochemistry, or provide detailed molecular insight in tumor subpopulations by the targeted selection of tumor subpopulations. However, selection of representative tumor areas leads only to an average picture which describes the most dominant clone and therefore underestimates the extent and pattern of clonal heterogeneity. MALDI MSI has demonstrated its suitability to study tumor heterogeneity in its native microenvironment.

In situ metabolite MALDI imaging offers enormous clinical potential by enabling the imaging of a largely previously intractable class of biomolecules. Combined with known metabolic pathways, this approach provides a means to image the activities of the pathways in tissues. The endocrine system is a collection of glands that secrete hormones directly into the circulatory system. The MALDI imaging based endocrinology project fills the heuristic gap to visualize the distributions of hormones, metabolites and drugs within tissues. Recently, tissue metabolomic studies have been initiated on adrenal tissues, which have revealed a refined functional structure beyond classical histological anatomy in human adrenal glands (Sun et al. Endocrinology, 2018 PubMed). Future developments will extend the so far existing clinicopathologic application areas by imaging the activities of pathways in tissues, imaging of hormones (steroids, catecholamines), drugs and their metabolites in the cortex and medulla of the adrenal glands and other endocrine organs of tissue from patients and animal models. The aims of these projects are to advance the understanding of the mechanism of endocrine diseases and to improve diagnosis, prognostic and therapeutic decision making.

In the field of diabetes research we focus on the morphological and molecular background of the disease in the endocrine pancreas, insulin resistance in peripheral organs and complications which are caused by type 2 diabetes to generate a deeper understanding of the disease which can be used as a new basis for interventional strategies. High-resolution mass spectrometry imaging (MALDI imaging) is used for investigating unsolved questions in diabetes research. The technology makes it possible to examine the distribution of metabolic products (cell metabolites) and many other molecular classes directly in tissue sections without the need of tissue homogenization and thus enables the generation of very high quality and complex data. In the field of diabetes research we focus on the morphological and molecular background of the disease in the endocrine pancreas, insulin resistance in peripheral organs and complications which are caused by type 2 diabetes to generate a deeper understanding of the disease which can be used as a new basis for interventional strategies. High-resolution mass spectrometry imaging (MALDI imaging) is used for investigating unsolved questions in diabetes research.