Imaging Metabolic Heterogeneity in Human Tumors

Abstract

The development of cancer leads to dysregulated metabolic fluxes in the human body. Comprehending the altered metabolism in a cancerous microenvironment is beneficial for trying to find cell-type specific vulnerabilities that enable researchers to create new therapeutics that target tumorous cells while sparing non-tumorous ones. Thus far, studying metabolism at a single cell resolution has not been feasible. This engineering thesis aims to solve this issue through the usage of MALDI imaging mass spectrometry (IMS) and Xenium to inspect, at a near single cell-adjacent resolution (10 μm), the distribution of metabolites and the expression of metabolic genes in two epithelial cancer models, pancreatic adenocarcinoma and HR+/HER2− breast cancer. The observation and quantification of the Warburg effect through both MALDI IMS and Xenium, as well as the discovery of specific phospholipids that co-located with cancerous cells in both carcinomas was achieved. Similarly, the overall conservation of central carbon metabolism across the two epithelial cancers, irrespective of their origin, was noted, posing the possibility of finding more generalized metabolic vulnerabilities in different carcinomas. Although Xenium revealed that cancerous cells are the most transcriptionally active, further research into the normalization, control-quality and cellular segmentation techniques of this spatial technology needs to be done.