Unraveling the role of lipids in glioma invasion

Glioblastoma multiforme (GBM) is the most common and deadly primary brain tumor in human adults. The ability of GBMs to invade and infiltrate normal surrounding brain tissues makes its complete surgical removal impossible and provides patients with a poor prognosis. At the invasive tumor rim, glioma cells are associated with microglial cells (MG), which are brain-resident macrophages that exhibit tumor-supportive functions. We discovered that glioma cells activate MG which in turn secrete lipids that promote GBM invasion. GBM invasion can be restrained when MG-derived lipid production, desaturation or secretion is inhibited. However, inhibition of fatty acid synthesis or desaturation in GBM cells has opposing effects and increases their invasive capacities. I propose that interfering with lipid synthesis and secretion in MG interrupts the MG-GBM crosstalk by restricting lipid-dependent migratory signaling cues in glioma cells, while blockade of fatty acid synthesis and desaturation in GBM cells triggers a stress response that enhances glioma invasion as a survival strategy to obtain nutrients and energy.

The overall goal of my project is to elucidate the nature and mechanistic underpinnings of MG-secreted lipids in GBM invasion and the necessity of de novo lipid synthesis and desaturation in GBM cells to identify potential metabolic lipid targets that restrain GBM invasion. This will enable a more complete surgical resection and substantially prolong survival of GBM patients.