Wood Rachael K, Flory Ashley R, Mann Melissa J, Talbot Lindsay J, Hendershot Linda M
Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
University of Tennessee Health Science Center, Memphis, TN 38163, USA.
iScience. 2022 Mar 17;25(4):104100. doi: 10.1016/j.isci.2022.104100. eCollection 2022 Apr 15.
Pediatric osteosarcomas (OS) exhibit extensive genomic instability that has complicated the identification of new targeted therapies. We found the vast majority of 108 patient tumor samples and patient-derived xenografts (PDXs), which display an unusually dilated endoplasmic reticulum (ER), 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 the expression of two of these, and , to physiological levels. This was sufficient to resolve the dilated ER morphology, restore collagen-I secretion, and enhance secretion of some extracellular matrix (ECM) proteins. However, orthotopic xenograft growth was not adversely affected by restoration of only and . 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. Possible relationships of this phenotype to tumorigenesis are discussed.
小儿骨肉瘤（OS）表现出广泛的基因组不稳定性，这使得新型靶向治疗的识别变得复杂。我们发现，在108例患者肿瘤样本和患者来源的异种移植瘤（PDX）中，绝大多数都表现出内质网（ER）异常扩张，同时触发原胶原蛋白-I蛋白在内质网内异常积累的四种COPII囊泡成分的表达降低。利用CRISPR激活技术将其中两种成分（ 和 ）的表达提高到生理水平。这足以解决内质网扩张的形态问题，恢复胶原蛋白-I的分泌，并增强一些细胞外基质（ECM）蛋白的分泌。然而，仅恢复 和 的表达对原位异种移植瘤的生长没有不利影响。我们的研究揭示了导致内质网扩张的机制，内质网扩张是骨肉瘤的一个标志性特征，并确定了这种基因不稳定肿瘤的高度保守分子特征。本文还讨论了这种表型与肿瘤发生的可能关系。
