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

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, etc.

Neoplasia. 2018 Jan;20(1):44-56.

PMID: 29190494

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP869288642	PF-573228		869288-64-2	Price

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