Role of the USP6 Oncogene in the Pathogenesis of Ewing Sarcoma: Novel Anti-Tumor Effects Through Interferon Sensitivity and Immune Infiltration / Ian Henrich.

Format:

Book

Thesis/Dissertation

Author/Creator:

Henrich, Ian, author.

Contributor:

Chou, Margaret, degree supervisor.

University of Pennsylvania. Pharmacology, degree granting institution.

Language:

English

Subjects (All):

Biology.

Cellular biology.

Public health.

Physiology.

Epidemiology.

Immunology.

Oncology.

Pharmacology--Penn dissertations.

Penn dissertations--Pharmacology.

Local Subjects:

Biology.

Cellular biology.

Public health.

Physiology.

Epidemiology.

Immunology.

Oncology.

Pharmacology--Penn dissertations.

Penn dissertations--Pharmacology.

Genre:

Academic theses.

Physical Description:

1 online resource (114 pages)

Contained In:

Dissertations Abstracts International 80-07B.

Place of Publication:

[Philadelphia, Pennsylvania] : University of Pennsylvania ; Ann Arbor : ProQuest Dissertations & Theses, 2018.

Language Note:

English

System Details:

Mode of access: World Wide Web.

text file

Summary:

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.

Notes:

Source: Dissertations Abstracts International, Volume: 80-07, Section: B.

Publisher info.: Dissertation/Thesis.

Advisors: Chou, Margaret; Committee members: Jeff Field; Malay Haldar; Xianxin Hua; Sunny Shin; Celeste Simon.

Department: Pharmacology.

Ph.D. University of Pennsylvania 2018.

Local Notes:

School code: 0175

ISBN:

9780438766907

Access Restriction:

Restricted for use by site license.

This item is not available from ProQuest Dissertations & Theses.

This item must not be sold to any third party vendors.