Abstract
Purpose: 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.Experimental Design: 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 in vivo confirmation of the preclinical in vitro results.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 IGF2 gene. Conversely, RNAi-mediated FUS-DDIT3 knockdown in myxoid liposarcoma cells led to an inactivation of IGF-IR/PI3K/Akt signaling associated with diminished IGF2 mRNA expression. Treatment of myxoid liposarcoma cell lines with several IGF-IR inhibitors resulted in significant growth inhibition in vitro and in vivoConclusions: 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. Clin Cancer Res; 23(20); 6227-38. ©2017 AACR.
Highlights
Accounting for approximately 5% to 10% of all soft tissue sarcomas, myxoid liposarcoma (MLS) represent $20% of all malignant adipocytic tumors [1]
In HT1080 fibrosarcoma cells, overexpression of FUS-DDIT3 induced aberrant insulin-like growth factor-I receptor (IGF-IR)/PI3K/Akt pathway activity, which was dependent on transcriptional induction of the IGF2 gene
RNAi-mediated FUS–DDIT3 knockdown in myxoid liposarcoma cells led to an inactivation of IGF-IR/PI3K/ Akt signaling associated with diminished IGF2 mRNA expression
Summary
Accounting for approximately 5% to 10% of all soft tissue sarcomas, myxoid liposarcoma (MLS) represent $20% of all malignant adipocytic tumors [1]. MLS are characterized by a high rate of local recurrences and development of metastases affecting in total $40% of patients [2]. MLS comprise a large spectrum ranging from paucicellular myxoid tumors to hypercellular round cell sarcomas associated with a more aggressive clinical course [3]. The vast majority of MLS is characterized by a chromosomal t(12;16)(q13;p11) translocation, juxtaposing the FUS and DDIT3 genes. About 5% of all patients with MLS display an alternative chromosomal t(12;22) rearrangement leading to an EWSR1–DDIT3 gene fusion [4]. The resulting FUS–DDIT3 and EWSR1–DDIT3 fusion proteins are thought to play an essential role in MLS pathogenesis, acting as transcriptional (dys-) regulators [5,6,7,8]; the functional details and the specific impact of the chimeric fusion protein on oncogenic signaling pathways known to be activated in MLS is incompletely understood
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