FUS–DDIT3 fusion protein-driven IGF-IR signaling is a therapeutic target in myxoid liposarcoma

Trautmann M., Menzel J., Bertling C., Cyra M., Isfort I., Steinestel K., Elges S., Grünewald I., Altvater B., Rossig C., Fröhling S., Hafner S., Simmet T., Åman P., Wardelmann E., Huss S., Hartmann W.

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 vivo. Conclusions: 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.