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 cell growth and survival.

Insights into major facilitator superfamily domain‐containing protein‐2a (Mfsd2a) in physiology and pathophysiology. What do we know so far?

“…Decreased Mfsd2a expression levels as well as impaired LPC fatty acid transporter function were shown to be associated with disrupted brain vascular endothelium leading to intratumoral BBB dysfunction in metastatic tumors of the brain as well (Tiwary et al, ). In contrast with the findings of previous studies that proposed pericyte‐dependent expression of Mfsd2a (Ben‐Zvi et al, ), astrocytes were shown to be responsible for the maintenance of Mfsd2a expression in brain endothelial cells through TGF‐beta1 and bFGF signaling pathways in this novel patient‐derived xenograft (PDX) mouse model of brain metastases (Tiwary et al, ).…”

NoRCE: Non-coding RNA Sets Cis Enrichment Tool

“…Table S10 lists a term which is found to be enriched in the previous analysis, as well. Moreover, previous studies have shown that transport mechanisms play a role in metastatic brain tumors [18]. Together these observations suggest that NoRCE can facilitate the identification of important pathways in which ncRNAs participate.…”

Bifunctional Aptamer–Doxorubicin Conjugate Crosses the Blood–Brain Barrier and Selectively Delivers Its Payload to EpCAM-Positive Tumor Cells

“…This uptake could be explained by a number of reasons, the first being that a small degree of TENN is taken up nonspecifically in a healthy animal model [25]. Second, during metastatic invasion, the BBB is compromised and thus some aptamers may nonspecifically enter the brain microenvironment at these sites [47]. Additionally, the enhanced permeability and retention effect may be responsible for some accumulation in the tumor [48].…”