All ETDs from UAB

Advisory Committee Chair

Peter H King

Advisory Committee Members

Anita B Hjelmeland

Jianmei W Leavenworth

L Burt Nabors

John J Shacka

Document Type

Dissertation

Date of Award

2019

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Glioblastomas (GBMs) are the most malignant primary brain tumor. GBMs represent 14.7% of total primary CNS tumors and 47.7% of malignant CNS tumors. The median survival of GBM is 18-20 months, while five-year survival rate is only 5.6%. GBMs are maintained by glioma stem cells (GSCs), and poor treatment outcomes are linked to the high resistance of GSCs to radiation and chemotherapy, and the immunosuppressive tumor microenvironment. The mRNA binding protein HuR is a key regulator of tumor growth and development based upon the fact that HuR targets mRNAs that are broadly involved in tumorigenesis. We have previously shown that HuR expression is elevated in malignant brain tumors, and HuR knockdown in GBM cells significantly attenuates the in vitro proliferation and migration. In the first part of this project, we investigated the anti-tumor effects of MS444, a small molecule inhibitor of HuR, using xenograft-derived human GBM lines. We found that MS444 produces a dose-dependent toxicity through the death receptor 5 (DR5) pathway, a decrease in GSC frequency, attenuation of cell migration at sublethal doses and inhibited expression of key growth factors and cytokines. In the second part of the project, we generated a tissue specific HuR knockout model using Cre-loxP system to study the effects of HuR knockout in myeloid cells on GBM development. In this model, we found robust loss of HuR in brain resident microglia and tumor infiltrated macrophages. HuR knockout significantly prolonged survival of tumor-bearing mice, as a result of decreased tumor proliferation and attenuated immunosuppression in the tumor microenvironment. By flow cytometry, we found that HuR knockout inhibited peripheral immune cell infiltration, especially myeloid derived suppressor cells and macrophages. It also led to blocked polarization of tumor associated microglia/ macrophages to the anti-inflammatory and pro-tumor M2-like and promoted the M1-like phenotype, in addition, as a result of attenuated immunosuppression, more effector T cells including both cytotoxic CD4+ and CD8+ cells entered the tumor sites. In summary, HuR inhibition in the tumor itself or in myeloid cells within the microenvironment, attenuated tumor growth, underscoring its therapeutic potential in GBM.

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