Mass Spectrometry Imaging Reveals a Gradient of Cancer-like Metabolic States in the Vicinity of Cancer Not Seen in Morphometric Margins from Microscopy

Abstract

Spatially resolved ambient mass spectrometry imaging methods have gained popularity to characterize cancer sites and their borders using molecular changes in the lipidome. This utility, however, is predicated on metabolic homogeneity at the border, which would create a sharp molecular transition at the morphometric borders. We subjected murine models of human medulloblastoma brain cancer to mass spectrometry imaging, a technique that provides a direct readout of tissue molecular content in a spatially resolved manner. We discovered a distance-dependent gradient of cancer-like lipid molecule profiles in the brain tissue within 1.2 mm of the cancer border, suggesting that a cancer-like state progresses beyond the histologic border, into the healthy tissue. The results were further corroborated using orthogonal liquid chromatography and mass spectrometry (LC-MS) analysis of selected tissue regions subjected to laser capture microdissection. LC-MS/MS analysis for robust identification of the affected molecules implied changes in a number of different lipid classes, some of which are metabolized from the essential docosahexaenoic fatty acid (DHA) present in the interstitial fluid. Metabolic molecular borders are thus not as sharp as morphometric borders, and mass spectrometry imaging can reveal molecular nuances not observed with microscopy. Caution must be exercised in interpreting multimodal imaging results stipulated on a coincidental relationship between metabolic and morphometric borders of cancer, at least within animal models used in preclinical research.

Desorption electrospray ionization mass spectrometry imaging in discovery and development of novel therapies

“…The same group most recently found a distancedependent gradient of cancer-like metabolic profile suggesting that a cancer-like state progresses beyond the histologic cancer border, into healthy tissue (Woolman et al, 2021).…”

Lipid Profiling in Cancer Diagnosis with Hand-Held Ambient Mass Spectrometry Probes: Addressing the Late-Stage Performance Concerns

“…Cancer cells are known to scavenge nutrients from their environment, especially under aggressive growth or inadequate perfusion [105], creating an additional link between diet and metabolism. Furthermore, the availability of precursor lipids diffused to the tumour site [106] is shown to create additional spatial heterogeneities in tissue metabolic states in the vicinity of cancer [107]. A high fat diet has been shown to alter lipid metabolism in cancer and influence the interplay between normal and cancer cells [108].…”

Ratiometric Mass Spectrometry Imaging for Stain-Free Delineation of Ischemic Tissue and Spatial Profiling of Ischemia-Related Molecular Signatures

“…On the other hand, histologyindependent MSI analysis uses molecular histology consisting of MSI datasets to identify which regions have distinct and/or correlated MS profiles. Molecular changes may precede morphometric alterations detectable by histology, potentially providing a more sensitive platform to characterize disease states at an early onset (Woolman et al, 2021). However, histology-independent MSI analysis usually uses the entire MSI dataset to identify specific regions, which may need to develop additional algorithms for reducing dimension and clustering of the huge MSI data (Abdelmoula et al, 2016;Inglese et al, 2019;Guo et al, 2021).…”