Date of Award
12-2021
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Program
Biomedical Sciences
Track
Cancer and Developmental Biology
Research Advisor
Linda M. Hendershot, PhD
Committee
Kevin W. Freeman, PhD Susan A. Miranda, PhD John D. Schuetz, PhD Tiffany Seagroves, PhD
Keywords
COPII; CRISPR activation, endoplasmic reticulum, osteosarcoma, procollagen
Abstract
Pediatric osteosarcoma tumors are characterized by an unusual abundance of grossly dilated endoplasmic reticulum and an immense genomic instability that has complicated identifying new effective molecular therapeutic targets. Here we report a novel molecular signature that encompasses the majority of 108 patient tumor samples, PDXs and osteosarcoma cell lines. These tumors exhibit reduced expression of four critical COPII vesicle proteins that has resulted in the accumulation of procollagen-I protein within ‘hallmark’ dilated ER. Using CRISPR activation technology, increased expression of only SAR1A and SEC24D to physiologically normal levels was sufficient to restore both collagen-I secretion and resolve dilated ER morphology to normal.
ORCID
http://orcid.org/0000-0002-9870-4772
DOI
10.21007/etd.cghs.2021.0555
Recommended Citation
Wood, Rachael (http://orcid.org/0000-0002-9870-4772), "Identifying the Molecular Cause of Extreme Endoplasmic Reticulum Dilation in Pediatric Osteosarcoma and Its Relationship to the Disease" (2021). Theses and Dissertations (ETD). Paper 573. http://dx.doi.org/10.21007/etd.cghs.2021.0555.
https://dc.uthsc.edu/dissertations/573
Declaration of Authorship
Included in
Disease Modeling Commons, Genetic Structures Commons, Investigative Techniques Commons, Medical Cell Biology Commons, Medical Genetics Commons, Medical Molecular Biology Commons, Neoplasms Commons, Pediatrics Commons