Reprogramming of mesenchymal stem cells by the synovial sarcoma-associated oncogene SYT–SSX2

Abstract

Cell identity is determined by its gene expression programs. The ability of a cell to change its identity and produce cell types outside its lineage is achieved by the activity of transcription controllers capable of reprogramming differentiation gene networks. The synovial sarcoma (SS)-associated protein, SYT–SSX2, reprograms myogenic progenitors and human bone marrow-derived mesenchymal stem cells (BMMSCs) by dictating their commitment to a pro-neural lineage. It fulfills this function by directly targeting an extensive array of neural-specific genes as well as genes of developmental pathway mediators. Concomitantly, the ability of both myoblasts and BMMSCs to differentiate into their normal myogenic and adipogenic lineages was compromised. SS is believed to arise in mesenchymal stem cells where formation of the t(X/18) translocation product, SYT–SSX, constitutes the primary event in the cancer. SYT–SSX is therefore believed to initiate tumorigenesis in its target stem cell. The data presented here allow a glimpse at the initial events that likely occur when SYT–SSX2 is first expressed, and its dominant function in subverting the nuclear program of the stem cell, leading to its aberrant differentiation, as a first step toward transformation. In addition, we identified the fibroblast growth factor receptor gene, Fgfr2, as one occupied and upregulated by SYT–SSX2. Knockdown of FGFR2 in both BMMSCs and SS cells abrogated their growth and attenuated their neural phenotype. These results support the notion that the SYT–SSX2 nuclear function and differentiation effects are conserved throughout sarcoma development and are required for its maintenance beyond the initial phase. They also provide the stem cell regulator, FGFR2, as a promising candidate target for future SS therapy.

Synovial sarcoma is a gateway to the role of chromatin remodeling in cancer

“…Subsequent immunohistochemical and ultrastructural studies do not support a synovial origin of this tumor, and hence, the name is often considered a misnomer [8,9]. Synovial sarcoma is currently classified as a miscellaneous tumor of uncertain cellular origin, most likely to be derived from primitive mesenchymal cells that undergo differentiation [10][11][12]. This is supported by tumors that occur in organs devoid of synovial tissues, including the lung [13], heart [14], kidney [15], digestive tract [16], and bone marrow [17].…”

“…Deregulation of expression programs by SS18-SSX results in a series of biological events implicated in synovial sarcoma pathogenesis that likely include reprogramming of stem cell differentiation [10]. SS18-SSX activates oncogenic pathways such as IGF2 [66], Wnt [67][68][69], FGF [10,70], and [71], as well as reactivation of the anti-apoptotic pathway and the BCL2 oncogene [72,73].…”

Truncated SSX Protein Suppresses Synovial Sarcoma Cell Proliferation by Inhibiting the Localization of SS18-SSX Fusion Protein

“…. Several studies have showed that synovial sarcoma cells express mRNA transcripts of pluripotency factors such as Sox2 , Oct3/4 , and Nanog [45] and show stem-cell-like gene expression profiles [46], and that tumor cells lacking the BAF47 tumor suppressor subunit express stem-cell-like signatures [47]. Kadoch and Crabtree [48] demonstrated that SS18-SSX fusion protein binds to SWI/SNF-like BAF (chromatin-remodeling) complexes and evicts both the wild-type SS18 and the tumor suppressor BAF47.…”

SSX2 (synovial sarcoma, X breakpoint 2)

“…Deregulation of expression programs by SS18-SSX1/2 results in a series of biological events implicated in synovial sarcoma pathogenesis. These events likely include reprogramming of stem cell differentiation (Garcia et al, 2012), and untimely activation of oncogenic pathways such as IGF2 (Sun et al, 2006), Wnt (Horvai et al, 2006;Pretto et al, 2006;Bozzi et al, 2008), FGF (Ishibe et al, 2005;Garcia et al, 2012), and ephrin (Barco et al, 2007), as well as reactivation of the anti-apoptotic pathway and the bcl-2 oncogene (Mancuso et al, 2000, Jones et al, 2013.SS18-SSX2 variants are rare. One was described by Fligman et al (1995).…”