Glioblastoma (GBM) is an incurable brain cancer with
a median survival
of less than two years from diagnosis. The standard treatment of GBM
is multimodality therapy comprising surgical resection, radiation,
and chemotherapy. However, prognosis remains poor, and there is an
urgent need for effective anticancer drugs. Since different regions
of a single GBM contain multiple cancer subpopulations (“intra-tumor
heterogeneity”), this likely accounts for therapy failure as
certain cancer cells can escape from immune surveillance and therapeutic
threats. Here, we present metabolomic data generated using the Orbitrap
secondary ion mass spectrometry (OrbiSIMS) technique to investigate
brain tumor metabolism within its highly heterogeneous tumor microenvironment.
Our results demonstrate that an OrbiSIMS-based untargeted metabolomics
method was able to discriminate morphologically distinct regions (viable,
necrotic, and non-cancerous) within single tumors from formalin-fixed
paraffin-embedded tissue archives. Specifically, cancer cells from
necrotic regions were separated from viable GBM cells based on a set
of metabolites including cytosine, phosphate, purine, xanthine, and
8-hydroxy-7-methylguanine. Moreover, we mapped ubiquitous metabolites
across necrotic and viable regions into metabolic pathways, which
allowed for the discovery of tryptophan metabolism that was likely
essential for GBM cellular survival. In summary, this study first
demonstrated the capability of OrbiSIMS for in situ investigation
of GBM intra-tumor heterogeneity, and the acquired information can
potentially help improve our understanding of cancer metabolism and
develop new therapies that can effectively target multiple subpopulations
within a tumor.