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) 患者的主要治疗方法，但缓解率仅为 25%，5 年总生存率仅为 20-34%，令人沮丧。其他疗法的转化均未成功，近20年来预后无明显改善。磷脂酰肌醇 3 激酶 (PI3K)/AKT 通路的异常激活与侵袭性临床行为 LPS 和化疗耐药有关，但其确切机制仍不清楚，临床上靶向 AKT 的努力均告失败。在这里，我们表明 AKT 介导的转录延伸因子 IWS1 磷酸化促进了 LPS 细胞和异种移植模型中癌症干细胞的维持。此外，AKT 对 IWS1 的磷酸化有助于形成“亚稳态”细胞表型，以间充质/上皮可塑性为特征。磷酸化 IWS1 的表达还促进贴壁依赖性和独立性生长、细胞迁移、侵袭和肿瘤转移。在 LPS 患者中，IWS1 表达与总生存率降低、复发频率增加和切除后复发时间缩短相关。这些发现表明 IWS1 介导的转录延伸是以 AKT 依赖性方式对人 LPS 病理学进行重要调节，并暗示 IWS1 是治疗 LPS 的重要分子靶点。复发频率增加，切除后复发时间缩短。这些发现表明 IWS1 介导的转录延伸是以 AKT 依赖性方式对人 LPS 病理学进行重要调节，并暗示 IWS1 是治疗 LPS 的重要分子靶点。复发频率增加，切除后复发时间缩短。这些发现表明 IWS1 介导的转录延伸是以 AKT 依赖性方式对人 LPS 病理学进行重要调节，并暗示 IWS1 是治疗 LPS 的重要分子靶点。