Date of Award

Winter 12-2-2025

Embargo Period

12-8-2028

Document Type

Dissertation - MUSC Only

Degree Name

Doctor of Philosophy (PhD)

Department

Pediatrics

Additional Department

Molecular and Cellular Biology and Pathobiology

College

College of Graduate Studies

First Advisor

Jezabel Rodriguez Blanco

Second Advisor

Denis Guttridge

Third Advisor

Anand Mehta

Fourth Advisor

Jorge Munera

Fifth Advisor

Hainan Lang

Sixth Advisor

Michael Ostrowski

Abstract

Malignant brain tumors are the leading cause of cancer-related death in children, with medulloblastoma (MB) being the most common. Despite aggressive treatment, relapses occur in ~30% of cases. Recurrent MB is typically metastatic, and survival after relapse rarely exceeds one year. These circumstances emphasize an urgent need for better understanding of tumor relapse mechanisms. Our lab recently identified a subset of astrocyte progenitor cells (APCs) that facilitate medulloblastoma relapse. Although compounds targeting bromodomain and extra-terminal (BET) proteins effectively depleted these cells, some tumors still manage to recur, suggesting the involvement of additional resistance mechanisms. Recent studies have identified oligodendrocyte precursor-like (OPC-like) MB cells as key drivers of relapse, but the mechanisms by which these cells evade therapy remain unclear. Medulloblastoma sphere and organotypic cultures, along with microglia/medulloblastoma co-cultures were used to identify candidate relapse drivers in APC-depleted tumors. Data in these cultures were validated in medulloblastoma animal models. Single-cell and bulk transcriptomic analyses suggested OPC dependency on NF-kB to self-renew, which was confirmed in medulloblastoma cultures. Our findings indicate that cytotoxic therapies activate microglia, which release cytokines that stimulate nuclear factor kappa B (NF-κB) signaling in tumor cells. This activation upregulates OPC-associated genes such as Sox10 and Olig2. Importantly, inhibition of NF-κB signaling in ex vivo and in vivo models prevented therapy-induced OPC enrichment and reduced tumor self-renewal. Given the established role of OPC-like cells in MB relapse, combining cytotoxic therapies with NF-κB pathway inhibitors may be essential to prevent recurrence and improve outcomes for children with this devastating disease.

Rights

Copyright is held by the author. All rights reserved.

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Available for download on Friday, December 08, 2028

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