Date of Award
Doctor of Philosophy (PhD)
Cancer and Developmental Biology
Linda M. Hendershot, PhD
Kevin W. Freeman, PhD Susan A. Miranda, PhD John D. Schuetz, PhD Tiffany Seagroves, PhD
COPII; CRISPR activation, endoplasmic reticulum, osteosarcoma, procollagen
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.
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.
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