Gerhard-Domagk-Institute of Pathology, University Hospital Münster, Münster, Germany.
Department of Pediatric Hematology and Oncology, University Children's Hospital Münster, Münster, Germany.
Clin Cancer Res. 2017 Oct 15;23(20):6227-6238. doi: 10.1158/1078-0432.CCR-17-0130. Epub 2017 Jun 21.
Myxoid liposarcoma is an aggressive disease with particular propensity to develop hematogenic metastases. Over 90% of myxoid liposarcoma are characterized by a reciprocal t(12;16)(q13;p11) translocation. The resulting chimeric FUS-DDIT3 fusion protein plays a crucial role in myxoid liposarcoma pathogenesis; however, its specific impact on oncogenic signaling pathways remains to be substantiated. We here investigate the functional role of FUS-DDIT3 in IGF-IR/PI3K/Akt signaling driving myxoid liposarcoma pathogenesis. Immunohistochemical evaluation of key effectors of the IGF-IR/PI3K/Akt signaling axis was performed in a comprehensive cohort of myxoid liposarcoma specimens. FUS-DDIT3 dependency and biological function of the IGF-IR/PI3K/Akt signaling cascade were analyzed using a HT1080 fibrosarcoma-based myxoid liposarcoma tumor model and multiple tumor-derived myxoid liposarcoma cell lines. An established myxoid liposarcoma avian chorioallantoic membrane model was used for confirmation of the preclinical results. A comprehensive subset of myxoid liposarcoma specimens showed elevated expression and phosphorylation levels of various IGF-IR/PI3K/Akt signaling effectors. In HT1080 fibrosarcoma cells, overexpression of FUS-DDIT3 induced aberrant IGF-IR/PI3K/Akt pathway activity, which was dependent on transcriptional induction of the gene. Conversely, RNAi-mediated knockdown in myxoid liposarcoma cells led to an inactivation of IGF-IR/PI3K/Akt signaling associated with diminished mRNA expression. Treatment of myxoid liposarcoma cell lines with several IGF-IR inhibitors resulted in significant growth inhibition and Our preclinical study substantiates the fundamental role of the IGF-IR/PI3K/Akt signaling pathway in myxoid liposarcoma pathogenesis and provides a mechanism-based rationale for molecular- targeted approaches in myxoid liposarcoma cancer therapy. .
黏液型脂肪肉瘤是一种侵袭性疾病，特别容易发生血源性转移。超过 90%的黏液型脂肪肉瘤具有特征性的 12;16(q13;p11)易位。由此产生的嵌合 FUS-DDIT3 融合蛋白在黏液型脂肪肉瘤发病机制中起着至关重要的作用；然而，其对致癌信号通路的具体影响仍有待证实。我们在此研究了 FUS-DDIT3 在 IGF-IR/PI3K/Akt 信号通路驱动黏液型脂肪肉瘤发病机制中的功能作用。我们对黏液型脂肪肉瘤标本进行了 IGF-IR/PI3K/Akt 信号轴关键效应物的免疫组织化学评估。使用 HT1080 纤维肉瘤为基础的黏液型脂肪肉瘤肿瘤模型和多种肿瘤衍生的黏液型脂肪肉瘤细胞系分析了 FUS-DDIT3 的依赖性和 IGF-IR/PI3K/Akt 信号级联的生物学功能。建立了一个黏液型脂肪肉瘤禽胚绒毛尿囊膜模型用于验证临床前结果。综合分析了一组黏液型脂肪肉瘤标本，显示各种 IGF-IR/PI3K/Akt 信号效应物的表达和磷酸化水平升高。在 HT1080 纤维肉瘤细胞中，FUS-DDIT3 的过表达诱导了 IGF-IR/PI3K/Akt 途径的异常活性，这依赖于 基因的转录诱导。相反，在黏液型脂肪肉瘤细胞中，RNAi 介导的 基因敲低导致 IGF-IR/PI3K/Akt 信号失活，同时伴有 mRNA 表达减少。用几种 IGF-IR 抑制剂处理黏液型脂肪肉瘤细胞系导致显著的生长抑制和 我们的临床前研究证实了 IGF-IR/PI3K/Akt 信号通路在黏液型脂肪肉瘤发病机制中的基本作用，并为黏液型脂肪肉瘤癌症治疗的分子靶向方法提供了基于机制的依据。 。
