FGFR2 is overexpressed in myxoid liposarcoma and inhibition of FGFR signaling impairs tumor growth in vitro

Abstract

Myxoid liposarcomas account for more than one third of liposarcomas and about 10% of all adult soft tissue sarcomas. The tumors are characterized by specific chromosomal translocations leading to the chimeric oncogenes FUS-DDIT3 or EWS1R-DDIT3. The encoded fusion proteins act as aberrant transcription factors. Therefore, we implemented comparative expression analyses using whole-genome microarrays in tumor and fat tissue samples. We aimed at identifying differentially expressed genes which may serve as diagnostic or prognostic biomarkers or as therapeutic targets. Microarray analyses revealed overexpression of FGFR2 and other members of the FGF/FGFR family. Overexpression of FGFR2 was validated by qPCR, immunohistochemistry and western blot analysis in primary tumor samples. Treatment of the myxoid liposarcoma cell lines MLS 402 and MLS 1765 with the FGFR inhibitors PD173074, TKI258 (dovitinib) and BGJ398 as well as specific siRNAs reduced cell proliferation, induced apoptosis and delayed cell migration. Combination of FGFR inhibitors with trabectedin further increased the effect. Our study demonstrates overexpression of FGFR2 and a functional role of FGFR signaling in myxoid liposarcoma. As FGFR inhibition showed effects on proliferation and cell migration and induced apoptosis in vitro, our data indicate the potential use of FGFR inhibitors as a targeted therapy for these tumors.

G protein pathway suppressor 2 (GPS2) acts as a tumor suppressor in liposarcoma

“…Besides the genetic amplification of the 12q13-15, other molecular mechanisms of LPS genesis have been proposed in recent years, including deregulation of some miRNAs and their downstream targets, epigenetics, and dysregulation of some oncogenic signaling pathways [4, 10, 28–31]. Particularly, amplification of the oncogene C-JUN is considered to contribute to the inhibition of PPARγ, a key regulator in terminal adipocyte differentiation [32].…”

Axitinib Has Antiangiogenic and Antitumorigenic Activity in Myxoid Liposarcoma

“…Both of the cell lines used were immortalized with SV40, which may affect their biology in unexpected ways. In addition, whereas MLS 402 has a typical type 1 FUS-CHOP transcript found in 24% of patients with myxoid liposarcoma [45], MLS 1765 has a rare type 8 transcript [46]. Although both cell lines showed similar responses to the drugs evaluated in vitro , only the MLS 1765 cells grew as tumor xenografts in mice.…”

Amplification of FRS2 in atypical lipomatous tumour/well‐differentiated liposarcoma and de‐differentiated liposarcoma: a clinicopathological and genetic study of 146 cases

“…The fibroblast growth factor receptor substrate 2 ( FRS2 ) gene is located close to MDM2 and CDK4 within the 12q13‐15 chromosomal band (Figure ) . FRS2 is a key adaptor protein in the fibroblast growth factor receptor (FGFR) pathway, binding to FGFR through its phosphotyrosine−binding domain and subsequently activating downstream signalling cascades . Previous studies have found that aberrant activation or amplification of FRS2 is related to tumorigenesis in thyroid, prostate and high‐grade serous ovarian cancers .…”