Modeling Clear Cell Sarcomagenesis

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Publication Type dissertation
School or College School of Medicine
Department Human Genetics
Author Straessler, Krystal M.
Title Modeling Clear Cell Sarcomagenesis
Date 2014-12
Description Clear cell sarcoma (CCS) is a rare but devastating malignancy with a proclivity for young adults, disturbingly low survivability, and recalcitrance to therapies. Due to the low incidence, it remains difficult to investigate the mechanism behind CCS. By generating an accurate model system that recapitulates human tumor dynamics, there is hope that the molecular mechanisms required for tumor initiation and maintenance can be identified and lead to more directed, successful therapeutic options. CCS achieves its clinically aggressive phenotype from the expression of a single oncogene, EWS-ATF1. This aberrant transcription factor drives clear cell tumorigenesis seemingly from deregulation of ATF1 signaling alone. The impact of CCS on the general population far exceeds its somewhat low prevalence due to its similarities to another aggressive tumor, malignant melanoma. CCS and melanoma resemble one another in morphology, immunohistochemistry, and overall clinical behavior. A targeted mouse model was developed that conditionally expresses human EWSATF1 cDNA under control of a ubiquitous promoter. Expression of EWS-ATF1 leads to 100% tumor formation with extraordinary speed, when induced in a permissive cell type. These tumors resembled human CCS in morphology, immunohistochemistry, and gene expression. Mesenchymal stem cells (MSC) were identified as the main source of traditional CCS. The EWS-ATF1 transcript proved capable of driving expression of melanocytic markers within MSCs, inducing the melanoma expression profile. When tumorigenesis was initiated in more differentiated cell types, the tumors did not resemble the traditional CCS phenotype. Therefore, differentiation state of the cell of origin proved critical in shaping tumor phenotype. It is thought that melanoma and CCS share a cell of origin. To test this, EWSATF1 was expressed within the melanocytic lineage, and gave rise to tumors 1 year post induction, with a low prevalence. These tumors mimic a rare dermal variant of CCS. Due to the long latency between EWS-ATF1 initiation and tumor formation, it is probable that EWS-ATF1 alone is not sufficient to drive dermal CCS. This work has identified EWS-ATF1 as the driving oncogene behind both clear cell tumor formation and the melanocytic phenotype. This model can be used to investigate novel therapeutics for a more targeted treatment of CCS.
Type Text
Publisher University of Utah
Subject MESH Genetic Markers; Sarcoma, Clear Cell; Cell Line, Tumor; Carcinogenesis; Oncogene Proteins, Fusion; RNA-Binding Protein EWS; Transcription Factors; Translocation, Genetic; Chromosomes, Human, Pair 12; Chromosomes, Human, Pair 22; Gene Rearrangement; Reverse Transcriptase Polymerase Chain Reaction; Biomarkers, Tumor
Dissertation Institution University of Utah
Dissertation Name Doctor of Philosophy
Language eng
Relation is Version of Digital version of Modeling Clear Cell Sarcomagenesis
Rights Management Copyright © Krystal M. Straessler 2014
Format Medium application/pdf
Format Extent 4,797,984 bytes
Source Original in Marriott Library Special Collections
ARK ark:/87278/s6tn1rwn
Setname ir_etd
Date Created 2019-04-25
Date Modified 2020-02-12
ID 1423169
Reference URL https://collections.lib.utah.edu/ark:/87278/s6tn1rwn