All ETDs from UAB

Advisory Committee Chair

Anita Hjelmeland

Advisory Committee Members

Etty N Benveniste

L Burt Nabors

Sasanka Ramanadham

John Shacka

Anna Sorace

Document Type

Dissertation

Date of Award

2022

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Glioblastoma (GBM) is a highly aggressive brain tumor with a median survival of 15 months even with standard of care—surgical resection, radiotherapy, and chemotherapy. Two of the key characteristics contributing to this malignancy are its highly invasive phenotype and resistance to the chemotherapy, temozolomide (TMZ). We, and others, have identified the sphingolipid balance as a driver of these phenotypes with dysregulated sphingolipid metabolism seen in GBM patient samples. The ceramidases, specifically acid ceramidase (ASAH1), mediate the balance between ceramides and sphingosine-1-phosphate (S1P). ASAH1 breaks down ceramides ultimately forming S1P. While ceramides induce cell death, S1P promotes migration and cell survival. Analysis of publicly available datasets revealed that ASAH1 is higher in GBM patients compared to non-tumor brain and correlated with migration-related pathways. Therefore, we chose to explore ASAH1’s role in GBM migration. Through genetic and pharmacologic inhibition of ASAH1, we found that ASAH1 contributed to GBM migration through PI3K-AKT-mTOR signaling mechanisms. Next, we sought to elucidate ASAH1’s impact on TMZ resistance as ASAH1 was higher in recurrent glioma patients. Inhibiting ASAH1 with carmofur in TMZ-resistant GBM cells led to increased apoptosis and cell cycle iv alterations. Using RNA-sequencing, we identified E2F8 as a transcription factor which was targeted by carmofur and contributed to cell cycle progression. This mechanism was specific to the TMZ-resistant cells suggesting a vulnerability that can be therapeutically targeted in these cells. In summary, we identified two mechanisms by which ASAH1 contributes to malignancy in primary and recurrent GBM cells. Since GBM is highly heterogenous, this work suggests that targeting ASAH1 is a valuable therapeutic target in different genetic populations within the tumor.

Share

COinS