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

Juan Tornin, Francisco Hermida-Prado, Ranjit Singh Padda, M. Victoria Gonzalez, Carlos Alvarez-Fernandez, Veronica Rey, Lucia Martinez-Cruzado, Oscar Estupiñan, Sofia T. Menendez, Lucia Fernandez-Nevado, Aurora Astudillo, Juan P. Rodrigo, Fabrice Lucien, Yohan Kim, Hon S. Leong, Juana Maria Garcia-Pedrero, Rene Rodriguez

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)44-56
Number of pages13
JournalNeoplasia (United States)
Volume20
Issue number1
DOIs
StatePublished - Jan 2018

ASJC Scopus subject areas

  • Cancer Research

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