Rodriguez Rene, Tornin Juan, Suarez Carlos, Astudillo Aurora, Rubio Ruth, Yauk Carole, Williams Andrew, Rosu-Myles Michael, Funes Juan M, Boshoff Chris, Menendez Pablo
Hospital Universitario Central de Asturias and Instituto Universitario de Oncología del Principado de Asturias, Oviedo, Spain.
Stem Cells. 2013 Oct;31(10):2061-72. doi: 10.1002/stem.1472.
Increasing evidence supports that mesenchymal stromal/stem cells (MSCs) may represent the target cell for sarcoma development. Although different sarcomas have been modeled in mice upon expression of fusion oncogenes in MSCs, sarcomagenesis has not been successfully modeled in human MSCs (hMSCs). We report that FUS-CHOP, a hallmark fusion gene in mixoid liposarcoma (MLS), has an instructive role in lineage commitment, and its expression in hMSC sequentially immortalized/transformed with up to five oncogenic hits (p53 and Rb deficiency, hTERT over-expression, c-myc stabilization, and H-RAS(v12) mutation) drives the formation of serially transplantable MLS. This is the first model of sarcoma based on the expression of a sarcoma-associated fusion protein in hMSC, and allowed us to unravel the differentiation processes and signaling pathways altered in the MLS-initiating cells. This study will contribute to test novel therapeutic approaches and constitutes a proof-of-concept to use hMSCs as target cell for modeling other fusion gene-associated human sarcomas.
越来越多的证据支持间充质基质/干细胞（MSCs）可能是肉瘤发生发展的靶细胞。尽管在小鼠中通过在MSCs中表达融合致癌基因已建立了不同肉瘤的模型，但在人MSCs（hMSCs）中尚未成功建立肉瘤发生模型。我们报告称，FUS-CHOP是黏液样脂肪肉瘤（MLS）中的标志性融合基因，在谱系定向中具有指导作用，其在经多达五次致癌打击（p53和Rb缺陷、hTERT过表达、c-myc稳定和H-RAS（v12）突变）依次永生化/转化的hMSC中的表达驱动了可连续移植的MLS的形成。这是首个基于hMSC中肉瘤相关融合蛋白表达的肉瘤模型，使我们能够阐明MLS起始细胞中改变的分化过程和信号通路。本研究将有助于测试新型治疗方法，并为将hMSCs用作建模其他融合基因相关人类肉瘤的靶细胞提供概念验证。
