Elsevier

Neoplasia

Volume 20, Issue 1, January 2018, Pages 44-56
Neoplasia

FUS-CHOP Promotes Invasion in Myxoid Liposarcoma through a SRC/FAK/RHO/ROCK-Dependent Pathway1

https://doi.org/10.1016/j.neo.2017.11.004Get rights and content
Under a Creative Commons license
open access

Abstract

Deregulated SRC/FAK signaling leads to enhanced migration and invasion in many types of tumors. In myxoid and round cell liposarcoma (MRCLS), an adipocytic tumor characterized by the expression of the fusion oncogene FUS-CHOP, SRC have been found as one of the most activated kinases. Here we used a cell-of-origin model of MRCLS and an MRCLS cell line to thoroughly characterize the mechanisms of cell invasion induced by FUS-CHOP using in vitro (3D spheroid invasion assays) and in vivo (chicken chorioallantoic membrane model) approaches. FUS-CHOP expression activated SRC-FAK signaling and increased the invasive ability of MRCLS cells. In addition, FAK expression was found to significantly correlate with tumor aggressiveness in sarcoma patient samples. The involvement of SRC/FAK activation in FUS-CHOP–mediated invasion was further confirmed using the SRC inhibitor dasatinib, the specific FAK inhibitor PF-573228, and FAK siRNA. Notably, dasatinib and PF573228 could also efficiently block the invasion of cancer stem cell subpopulations. Downstream of SRC/FAK signaling, we found that FUS-CHOP expression increases the levels of the RHO/ROCK downstream effector phospho-MLC2 (T18/S19) and that this activation was prevented by dasatinib or PF573228. Moreover, the ROCK inhibitor RKI-1447 was able to completely abolish invasion in FUS-CHOP–expressing cells. These data uncover the involvement of SRC/FAK/RHO/ROCK signaling axis in FUS-CHOP–mediated invasion, thus providing a rationale for testing inhibitors of this pathway as potential novel antimetastatic agents for MRCLS treatment.

Abbreviations

MRCLS
myxoid/round cell liposarcoma
FUS
fused in sarcoma
CHOP
C/EBP homologous protein
FAK
focal adhesion kinase
SFK
Src-family of protein kinases
RHO
RHOA/C GTPases
ROCK
Rho-associated coiled-coil-containing protein kinases 1 and 2
MLC2
myosin light chain 2
BMSC
bone marrow–derived mesechymal stem/stromal cell
FFPE
formalin-fixed, paraffin-embedded
CAM
chorioallantoic membrane
CSC
cancer stem cell

Cited by (0)

1

Author contributions: J. T. and F. H.-P.: development of methodology; performance of experimental procedures; acquisition, analysis, and interpretation of data. R. S. P, L. M.-C., O. E, S. T.-M., L. F.-N., and F.L.: performance of experimental procedures. M. V. G., C. A.-F., V. R., A. A., J. P. R., and H. S. L.: analysis and interpretation of data. J. M. G.-P. and R. R.: conception and design, analysis and interpretation of data, manuscript writing, and financial support. The manuscript has been seen and approved by all authors.

1

These authors contributed equally to this work.