Pediatric osteosarcomas are characterized by an unusually dilated endoplasmic reticulum (ER). Our analysis of RNA expression data from 108 patient tumor samples and patient-derived xenografts (PDXs) revealed the overwhelming majority of these tumor have reduced expression of four COPII vesicle components that trigger aberrant accumulation of procollagen-I protein within the ER. CRISPR activation technology was used to increase expression of two of these, SAR1A and SEC24D, to physiologically normal levels. This was sufficient to resolve the dilated ER morphology and restore secretion of collagen-I, as well as enhance secretion of extracellular matrix (ECM) proteins. Our studies reveal the mechanism responsible for the dilated ER that is a hallmark characteristic of OS and identify a highly conserved molecular signature for this genetically unstable tumor.