Guarnerio Jlenia, Riccardi Luisa, Taulli Riccardo, Maeda Takahiro, Wang Guocan, Hobbs Robin M, Song Min Sup, Sportoletti Paolo, Bernardi Rosa, Bronson Roderick T, Castillo-Martin Mireia, Cordon-Cardo Carlos, Lunardi Andrea, Pandolfi Pier Paolo
Cancer Research Institute, Beth Israel Deaconess Cancer Center, Departments of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
Cancer Discov. 2015 Apr;5(4):396-409. doi: 10.1158/2159-8290.CD-14-1022. Epub 2015 Jan 22.
The regulatory factors governing adult mesenchymal stem cell (MSC) physiology and their tumorigenic potential are still largely unknown, which substantially delays the identification of effective therapeutic approaches for the treatment of aggressive and lethal forms of MSC-derived mesenchymal tumors, such as undifferentiated sarcomas. Here, we have developed a novel platform to screen and quickly identify genes and pathways responsible for adult MSC transformation, modeled undifferentiated sarcoma in vivo, and, ultimately, tested the efficacy of targeting the identified oncopathways. Importantly, by taking advantage of this new platform, we demonstrate the key role of an aberrant LRF-DLK1-SOX9 pathway in the pathogenesis of undifferentiated sarcoma, with important therapeutic implications.
The paucity of therapeutic options for the treatment of sarcoma calls for a rapid and effective preclinical assessment of new therapeutic modalities. We have here developed a new platform to deconstruct the molecular genetics underlying the pathogenesis of sarcoma and to evaluate in vivo the efficacy of novel targeted therapies.
调控成人间充质干细胞（MSC）生理功能及其致瘤潜力的调控因子在很大程度上仍不清楚，这严重延迟了针对侵袭性和致死性MSC来源的间充质肿瘤（如未分化肉瘤）的有效治疗方法的鉴定。在此，我们开发了一个新平台，用于筛选和快速鉴定导致成人MSC转化的基因和途径，在体内模拟未分化肉瘤，最终测试靶向已鉴定的肿瘤发生途径的疗效。重要的是，通过利用这个新平台，我们证明了异常的LRF-DLK1-SOX9途径在未分化肉瘤发病机制中的关键作用，并具有重要的治疗意义。
肉瘤治疗选择的匮乏要求对新的治疗方式进行快速有效的临床前评估。我们在此开发了一个新平台，以解构肉瘤发病机制背后的分子遗传学，并在体内评估新型靶向治疗的疗效。
