Metastatic Brain Tumors Disrupt the Blood-Brain Barrier and Alter Lipid Metabolism by Inhibiting Expression of the Endothelial Cell Fatty Acid Transporter Mfsd2a
Abstract
Disruption of the blood-brain barrier (BBB) by cancer cells is linked to metastatic tumor initiation and progression; however, the pathways that drive these events remain poorly understood. Here, we have developed novel patient-derived xenograft (PDX) models of brain metastases that recapitulate pathological growth features found in original patient samples, thus allowing for analysis of BBB disruption by tumor cells. We report that the BBB is selectively disrupted in brain metastases, in part, via inhibition of the endothelial cell-expressed docosahexaenoic acid (DHA) transporter, major facilitator superfamily domain 2a (Mfsd2a). Loss of Mfsd2a expression in the tumor endothelium results in enhanced BBB leakage, but reduced DHA transport and altered lipid metabolism within metastases. Mfsd2a expression in normal cerebral endothelial cells is cooperatively regulated by TGFβ and bFGF signaling pathways, and these pathways are pathologically diminished in the brain metastasis endothelium. These results not only reveal a fundamental pathway underlying BBB disruption by metastatic cancer cells, but also suggest that restoring DHA metabolism in the brain tumor microenvironment may be a novel therapeutic strategy to block metastatic ...Continue Reading
References
Citations
Methods Mentioned
Software Mentioned
Related Concepts
Related Feeds
Cancer Metabolism
In order for cancer cells to maintain rapid, uncontrolled cell proliferation, they must acquire a source of energy. Cancer cells acquire metabolic energy from their surrounding environment and utilize the host cell nutrients to do so. Here is the latest research on cancer metabolism.
Blood Brain Barrier
The blood brain barrier is a border that separates blood from cerebrospinal fluid. Discover the latest search on this highly selective semipermeable membrane here.
Blood Brain Barrier Regulation in Health & Disease
The blood brain barrier is essential in regulating the movement of molecules and substances in and out of the brain. Disruption to the blood brain barrier and changes in permeability allow pathogens and inflammatory molecules to cross the barrier and may play a part in the pathogenesis of neurodegenerative disorders. Here is the latest research in this field.
Blood Brain Barrier Chips
The blood brain barrier (BBB) is comprised of endothelial cells that regulate the influx and outflux of plasma concentrations. Lab-on-a-chip devices allow scientists to model diseases and mechanisms such as the passage of therapeutic antibodies across the BBB. Discover the latest research on BBB chips here.
Blood-Brain Barrier Transport in Neurodegeneration
The blood brain barrier is important for regulating the movement of biomolecules in and out of the brain. For example, membrane transporters in the blood brain barrier can be essential for regulating drug movement and dysregulation of these processes may play a role in neurodegeneration. This feed follows the latest research on this topic.