|Localized Metabolomic Gradients in Patient-Derived Xenograft Models of Glioblastoma.
|Year of Publication
|Randall EC, Lopez BGC, Peng S, Regan MS, Abdelmoula WM, Basu SS, Santagata S, Yoon H, Haigis MC, Agar JN, Tran NL, Elmquist WF, White FM, Sarkaria JN, Agar NYR
|2020 Mar 15
Glioblastoma (GBM) is increasingly recognized as a disease involving dysfunctional cellular metabolism. GBMs are known to be complex heterogeneous systems containing multiple distinct cell populations and are supported by an aberrant network of blood vessels. A better understanding of GBM metabolism, its variation with respect to the tumor microenvironment, and resulting regional changes in chemical composition is required. This may shed light on the observed heterogeneous drug distribution, which cannot be fully described by limited or uneven disruption of the blood-brain barrier. In this work, we used mass spectrometry imaging (MSI) to map metabolites and lipids in patient-derived xenograft models of GBM. A data analysis workflow revealed that distinctive spectral signatures were detected from different regions of the intracranial tumor model. A series of long-chain acylcarnitines were identified and detected with increased intensity at the tumor edge. A 3D MSI dataset demonstrated that these molecules were observed throughout the entire tumor/normal interface and were not confined to a single plane. mRNA sequencing demonstrated that hallmark genes related to fatty acid metabolism were highly expressed in samples with higher acylcarnitine content. These data suggest that cells in the core and the edge of the tumor undergo different fatty acid metabolism, resulting in different chemical environments within the tumor. This may influence drug distribution through changes in tissue drug affinity or transport and constitute an important consideration for therapeutic strategies in the treatment of GBM. SIGNIFICANCE: GBM tumors exhibit a metabolic gradient that should be taken into consideration when designing therapeutic strategies for treatment..
|PubMed Central ID
|P41 EB015898 / EB / NIBIB NIH HHS / United States
R25 CA089017 / CA / NCI NIH HHS / United States
U54 CA210180 / CA / NCI NIH HHS / United States
R01 CA201469 / CA / NCI NIH HHS / United States
T32 HL007627 / HL / NHLBI NIH HHS / United States