Author ORCID Identifier
https://orcid.org/0000-0003-1737-663X
Date of Graduation
7-2019
Document Type
Dissertation (PhD)
Program Affiliation
Neuroscience
Degree Name
Doctor of Philosophy (PhD)
Advisor/Committee Chair
Andrew Bean
Committee Member
Pramod Dash
Committee Member
Ilya Levental
Committee Member
Andrey Tsvetkov
Committee Member
Jeffrey Frost
Abstract
The epidermal growth factor receptor (EGFR) variant three (EGFRvIII) mutation is linked with approximately one third of Glioblastoma Multiforme (GBM) tumors and is associated with poor patient prognosis. Persistent signaling due to a lack of the EGFR ectodomain and inefficient degradation have been suggested to underlie the tumorgenic properties of EGFRvIII. I observed that, like the parental EGFR, EGFRvIII is internalized into the intraluminal vesicles of late endosomes / multivesicular bodies (MVBs) but does not follow the canonical pathway by which wild-type EGFR is degraded following MVB fusion with lysosomes. I determined that EGFRvIII is secreted on exosomes, the intraluminal vesicles that are secreted upon MVB fusion with the plasma membrane. This suggested that EGFRvIII is localized in a subset of MVBs that preferentially fuse with the plasma membrane rather than with lysosomes which may account for its decreased degradation.
Astrocytes are a component of the GBM tumor microenvironment with whom tumor cells interact in a paracrine manner. I examined the effect of EGFRvIII-containing exosomes derived from GBM cells on astrocytes and observed that EGFRvIII containing exosomes induce changes in astrocytes that mimic reactive astrogliosis including an increase in glial fibrillary acidic protein (GFAP) and altered astrocyte morphology.
These results reveal novel aspects of the endocytic trafficking of EGFRvIII that underlie its reduced degradation and the mechanism by which it is packaged into exosomes for secretion. Moreover, I show that EGFRvIII secretion on exosomes can facilitate changes in the tumor microenvironment to enable tumor growth.
Keywords
exosomes, microenvironment, trafficking, endocytosis, late endosome, proliferation, migration, astrocyte