Date of Award

Spring 5-22-2023

Embargo Period

12-15-2033

Document Type

Dissertation - MUSC Only

Degree Name

Doctor of Philosophy (PhD)

Department

Biochemistry and Molecular Biology

College

College of Graduate Studies

First Advisor

Denis Guttridge

Second Advisor

Besim Ogretmen

Third Advisor

Deanna Baker Frost

Fourth Advisor

Michael Ostrowski

Fifth Advisor

Antonis Kourtidis

Abstract

Pancreatic Ductal Adenocarcinoma (PDAC) is a deadly disease with a meager 12 percent 5-year survival rate. This is largely because PDAC is difficult to diagnose at an early stage and many patients present with both distant metastases and cancer-induced cachexia. The mouse models used to study PDAC do not sufficiently recapitulate the human phenotypes of metastasis and cachexia, making it challenging to understand the pathogenesis of this disease and develop therapeutics to treat it.

Our laboratory discovered that ceramide levels are significantly decreased in skeletal muscles of cachectic patients. Ceramides are an important component of the muscle membrane, an area of the muscle which is substantially damaged in cachectic PDAC patients but not in non-cachectic PDAC patients. We sought to understand if this loss in ceramides played a role in the initiation or development of the muscle damage and wasting that occurs in cancer cachexia.

Using our KPP genetic mouse model of cachexia and ceramide knockout mice, we investigated the effects of the regulation of ceramide levels in muscle fibers. We show that the loss of ceramides in the muscle alters the expression of MyoD, a protein along the muscle regeneration pathway but not the rate of activation of this pathway. We also developed AAV vectors to knockdown or overexpress a key ceramide synthesis enzyme to determine if the cachexia phenotype would be either exacerbated or ameliorated by its regulation. We hope to use the new models described in this thesis to test this question in the future.

We described an optimized orthotopic model of pancreatic cancer that increases the development of distant metastases and exhibits common markers of cancer-induced cachexia. This model can be utilized in our future studies to determine if the downregulation of ceramides contributes to the origin of the cachexia syndrome or if it is a consequence of the muscle wasting in this disease. We hope this model will be used by investigators to develop therapeutics to combat PDAC and that having a model that presents with both metastasis and cachexia will increase the efficacy of these treatments as they are translated to clinical trials.

Rights

Copyright is held by the author. All rights reserved.

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Available for download on Thursday, December 15, 2033

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