Wang Yu, Zhang Hongji, La Ferlita Alessandro, Sp Nipin, Goryunova Marina, Sarchet Patricia, Hu Zhiwei, Sorkin Michael, Kim Alex, Huang Hai, Zhu Hua, Tsung Allan, Pollock Raphael E, Beane Joal D
Department of Surgery, Division of Surgical Oncology, James Cancer Center, The Ohio State University, Columbus, OH, USA.
Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
Oncogenesis. 2023 May 26;12(1):30. doi: 10.1038/s41389-023-00469-z.
Chemotherapy remains the mainstay of treatment for patients with advanced liposarcoma (LPS), but response rates are only 25% and the overall survival at 5 years is dismal at 20-34%. Translation of other therapies have not been successful and there has been no significant improvement in prognosis for nearly 20 years. The aberrant activation of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway has been implicated in the aggressive clinical behavior LPS and in resistance to chemotherapy, but the precise mechanism remains elusive and efforts to target AKT clinically have failed. Here we show that the AKT-mediated phosphorylation of the transcription elongation factor IWS1, promotes the maintenance of cancer stem cells in both cell and xenograft models of LPS. In addition, phosphorylation of IWS1 by AKT contributes to a "metastable" cell phenotype, characterized by mesenchymal/epithelial plasticity. The expression of phosphorylated IWS1 also promotes anchorage-dependent and independent growth, cell migration, invasion, and tumor metastasis. In patients with LPS, IWS1 expression is associated with reduced overall survival, increased frequency of recurrence, and shorter time to relapse after resection. These findings indicate that IWS1-mediated transcription elongation is an important regulator of human LPS pathobiology in an AKT-dependent manner and implicate IWS1 as an important molecular target to treat LPS.
化疗仍然是晚期脂肪肉瘤（LPS）患者治疗的主要手段，但缓解率仅为25%，5年总生存率低至20%-34%。其他疗法的转化并不成功，近20年来预后也没有显著改善。磷脂酰肌醇3激酶（PI3K）/AKT信号通路的异常激活与LPS的侵袭性临床行为及化疗耐药有关，但确切机制仍不清楚，针对AKT的临床治疗尝试也已失败。在此我们发现，在LPS的细胞和异种移植模型中，AKT介导的转录延伸因子IWS1磷酸化促进了癌症干细胞的维持。此外，AKT介导的IWS1磷酸化导致了一种“亚稳定”细胞表型，其特征是间充质/上皮可塑性。磷酸化IWS1的表达还促进了锚定依赖性和非依赖性生长、细胞迁移、侵袭及肿瘤转移。在LPS患者中，IWS1表达与总生存率降低、复发频率增加及切除后复发时间缩短有关。这些发现表明，IWS1介导的转录延伸是以AKT依赖的方式对人LPS病理生物学起重要调节作用，并提示IWS1是治疗LPS的重要分子靶点。
