Date of Award

2018

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Pharmacology

First Advisor

Margaret Chou

Abstract

Sarcomas are mesenchymal malignancies that comprise over 60 divergent clinical entities. Ewing sarcoma (ES) is one of the most common sarcomas in pediatric patients and is often intractable once the tumor metastasizes or reoccurs, resulting in a five-year survival rate of 20% for late-stage patients. Though ES is defined and driven by the translocation and fusion of EWS and an Ets family member, therapies targeting the pathogenic translocation, or its downstream targets, have failed in the clinic. The lack of targeted therapies has led to the standard of care consisting of radiation, surgery, and chemotherapy for the past twenty years, and consequently little change in the survival rate of metastatic patients. Immunotherapy has revolutionized cancer treatment for many other cancers, but sarcomas, particularly ES, have lagged behind. Furthermore, the immune compartment within ES has not been well characterized. Our laboratory has discovered that the USP6 oncogene is selectively upregulated in ES. While USP6 is the key etiological agent in two benign tumors: nodular fasciitis (NF) and aneurysmal bone cyst (ABC), little is known about its role in malignant entities. Overexpression of USP6 in ES is associated with a Jak-STAT and an interferon (IFN) response gene signature. Strikingly, treatment with exogenous IFN selectively killed USP6-expressing ES cells in vitro. Investigation into the mechanism revealed that the pro-apoptotic ligand TRAIL was massively upregulated upon IFN treatment only in USP6-expressing ES cells. Interestingly, other genes were also upregulated in a similar manner upon IFN treatment, specifically several chemokines known to attract T cells and monocytes. Conditioned media from USP6+ cells increased migration of activated T cells and monocytes in vitro. Furthermore, USP6-expressing ES mouse xenografts had smaller terminal mass and increased immune cell infiltration. ES patients with high USP6 had an immune infiltration gene signature and enhanced survival, suggesting a potentially beneficial role of USP6 in regulating the immune microenvironment. These studies highlight the novel role of USP6 in regulating ES sensitivity toward immunomodulatory treatments such as IFN and point toward modulating USP6 expression as potential therapeutic avenue.

Embargoed

Available to all on Tuesday, December 21, 2021

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