ESI–MS/MS and MALDI-IMS Localization Reveal Alterations in Phosphatidic Acid, Diacylglycerol, and DHA in Glioma Stem Cell Xenografts

Glioblastoma
(GBM) is the most common adult primary brain tumor.
Despite aggressive multimodal therapy, the survival of patients with
GBM remains dismal. However, recent evidence has demonstrated the
promise of bone marrow-derived mesenchymal stem cells (BM-hMSCs) as
a therapeutic delivery vehicle for anti-glioma agents due to their
ability to migrate or home to human gliomas. While several studies
have demonstrated the feasibility of harnessing the homing capacity
of BM-hMSCs for targeted delivery of cancer therapeutics, it is now
also evident, based on clinically relevant glioma stem cell (GSC)
models of GBMs, that BM-hMSCs demonstrate variable tropism toward
these tumors. In this study, we compared the lipid environment of
GSC xenografts that attract BM-hMSCs (N = 9) with
those that do not attract (N = 9) to identify lipid
modalities that are conducive to homing of BM-hMSC to GBMs. We identified
lipids directly from tissue by matrix-assisted laser desorption/ionization
(MALDI) imaging mass spectrometry (IMS) and electrospray ionization–tandem
mass spectrometry (ESI–MS/MS) of lipid extracts. Several species
of signaling lipids, including phosphatidic acid (PA 36:2, PA 40:5,
PA 42:5, and PA 42:7) and diacylglycerol (DAG 34:0, DAG 34:1, DAG
36:1, DAG 38:4, DAG 38:6, and DAG 40:6), were lower in attracting
xenografts. Molecular lipid images showed that PA (36:2), DAG (40:6),
and docosahexaenoic acid (DHA) were decreased within tumor regions of attracting xenografts. Our results provide the
first evidence for lipid signaling pathways and lipid-mediated tumor
inflammatory responses in the homing of BM-hMSCs to GSC xenografts.
Our studies provide new fundamental knowledge on the molecular correlates
of the differential homing capacity of BM-hMSCs toward GSC xenografts.