Abstract B04: Oncogenic relevance of IGF-IR and PI3K/AKT/GSK3-beta signaling in myxoid liposarcoma
Authors: Trautmann Marcel , Bertling Christian , Menzel Jasmin , Cyra Magdalene , Steinestel Konrad , Grünewald Inga , Åman Pierre , Wardelmann Eva , Huss Sebastian , Hartmann Wolfgang 
Published: December 2017

Introduction: Myxoid liposarcoma (MLS) accounts for 30-35% of all LS cases and is the second most common type of liposarcoma. One third of MLS lesions will become metastatic with tumors spreading to unusual bone and soft tissue locations. Ninety percent of MLS are characterized by a specific reciprocal translocation t (12; 16) (q13; p11), leading to the pathogenic gene fusion of FUS and DDIT3. The resulting chimeric FUS-DDIT3 fusion protein is suggested to play a crucial role in MLS pathogenesis, although the specific biological function and the mechanism of action remain to be defined. Aiming at the preclinical identification of novel therapeutic options in vitro and in vivo, we investigate the functional relevance of IGF-IR and PI3K/AKT/GSK3-beta signaling in primary MLS and tumor-derived cell lines.

Methods: Immunohistochemical analyses of IGF-IR and PI3K/AKT/GSK3-beta signaling effectors and modulators were performed in a comprehensive cohort of primary MLS specimens. FUS-DDIT3-dependent activation of the PI3K/AKT/GSK3-beta signaling cascade was analyzed by siRNA knockdown experiments and protein immunoblotting in vitro. Cell proliferation and FACS assays were performed in two different MLS cell lines. An in vivo tumor model was successfully established performing the chicken chorioallantoic membrane (CAM) assay.

Results: In a significant subset of MLS specimens, immunohistochemical staining revealed elevated phosphorylation levels of the respective signaling components, indicating that activated IGF-IR and PI3K/AKT/GSK3-beta signaling is a frequent feature in MLS. IGF-IR inhibition significantly suppressed the PI3K/AKT/GSK3-beta downstream cascade, associated with reduced phosphorylation levels of several signaling components, impairment of MLS cell viability and induction of apoptosis in vitro and in vivo. Furthermore, siRNA-mediated knockdown of FUS-DDIT3 lead to dephosphorylation of PI3K/AKT/GSK3-beta signaling components, implying that the FUS-DDIT3 fusion protein is involved in the IGF-IR regulated signaling cascade.

Conclusion: Our study emphasizes the pivotal role of IGF-IR and PI3K/AKT/GSK3-beta signaling in MLS pathogenesis and indicates its functional dependence on the characteristic FUS-DDIT3 fusion protein. Furthermore, our in vitro and in vivo results demonstrate that targeting the IGF-IR and PI3K/AKT/GSK3-beta signaling pathway might provide a specific, molecular founded therapeutic strategy in the treatment of MLS.

Citation Format: Marcel Trautmann, Christian Bertling, Jasmin Menzel, Magdalene Cyra, Konrad Steinestel, Inga Grünewald, Pierre Åman, Eva Wardelmann, Sebastian Huss, Wolfgang Hartmann. Oncogenic relevance of IGF-IR and PI3K/AKT/GSK3-beta signaling in myxoid liposarcoma [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr B04.