LAUSR

BACKGROUND Glioblastoma is the most common and aggressive primary brain tumor. Large scale sequencing initiatives have cataloged its mutational landscape in hopes of elucidating mechanisms driving this deadly disease. However, a major bottleneck in harnessing this data for new therapies is deciphering "driver" and "passenger" events amongst the vast volume of information. METHODS We utilized an autochthonous, in vivo screening approach to identify driver, EGFR variants. RNA-Seq identified unique molecular signatures of mouse gliomas across these variants, which only differ by a single amino acid change. In particular, we identified alterations to lipid metabolism, which we further validated through an unbiased lipidomics screen. RESULTS Our screen identified A289I as the most potent EGFR variant, which has previously not been characterized. One of the mechanisms through with A289I promotes gliomagenesis is to alter cellular triacylglycerides through MTTP. Knockout of Mttp in mouse gliomas, reduces gliomagenesis in multiple models. CONCLUSION EGFR variants that differ by a single amino acid residue differentially promote gliomagenesis. Among the identified mechanism that drive glioma growth include lipid metabolism through MTTP. Understanding triacylglyceride accumulation may present a prospective therapeutic pathway for this deadly disease.