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Localized metabolomic gradients in patient-derived xenograft models of glioblastoma
Name
nihms-1544173.pdf
Description
Accepted version
Size
1.1 MB
Format
Adobe PDF
Checksum (MD5)
9ccd5ef23a731e25b85ab9a8aca8f3ea
Author(s)
Randall, Elizabeth C
Lopez, Begoña GC
Peng, Sen
Regan, Michael S
Abdelmoula, Walid M
Basu, Sankha S
Santagata, Sandro
Yoon, Haejin
Haigis, Marcia C
Agar, Jeffrey N
Date Issued
2020
Journal
Cancer Research
Publisher
American Association for Cancer Research (AACR)
Version
Author's final manuscript
Abstract
© 2019 American Association for Cancer Research. 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.
Terms of Use
Creative Commons Attribution-Noncommercial-Share Alike
Persistent DSpace Link
DOI of Published Version
10.1158/0008-5472.CAN-19-0638
