Targeting the Wnt pathway in synovial sarcoma models.
Synovial sarcoma is an aggressive soft-tissue malignancy of children and young adults, with no effective systemic therapies. Its specific oncogene, SYT-SSX (SS18-SSX), drives sarcoma initiation and development. The exact mechanism of SYT-SSX oncogenic function remains unknown. In an SYT-SSX2 transgenic model, we show that a constitutive Wnt/β-catenin signal is aberrantly activated by SYT-SSX2, and inhibition of Wnt signaling through the genetic loss of β-catenin blocks synovial sarcoma tumor formation. In a combination of cell-based and synovial sarcoma tumor xenograft models, we show that inhibition of the Wnt cascade through coreceptor blockade and the use of small-molecule CK1α activators arrests synovial sarcoma tumor growth. We find that upregulation of the Wnt/β-catenin cascade by SYT-SSX2 correlates with its nuclear reprogramming function. These studies reveal the central role of Wnt/β-catenin signaling in SYT-SSX2-induced sarcoma genesis, and open new venues for the development of effective synovial sarcoma curative agents.


CONCLUSIONS
Synovial sarcoma is an aggressive soft-tissue cancer that afflicts children and young adults, and for which there is no effective treatment. The current studies provide critical insight into our understanding of the pathogenesis of SYT–SSX-dependent synovial sarcoma and pave the way for the development of effective therapeutic agents for the treatment of the disease in humans.
1Department of Cancer Biology, 2Division of Hepatobiliary Surgery, Department of Surgery, 3Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, and 4Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center; 5Department of Cell and Developmental Biology, Vanderbilt University; 6StemSynergy Therapeutics, Inc., Nashville, Tennessee; 7Department of Pediatrics-Nutrition, Baylor College of Medicine, Houston, Texas; and 8Department of Human Genetics, Howard Hughes Medical Institute, University of Utah, Salt Lake City, Utah.
Whitney
W
Barham
Andrea L
AL
Frump
Taylor P
TP
Sherrill
Christina B
CB
Garcia
Kenyi
K
Saito-Diaz
Michael N
MN
VanSaun
Barbara
B
Fingleton
Linda
L
Gleaves
Darren
D
Orton
Mario R
MR
Capecchi
Timothy S
TS
Blackwell
Ethan
E
Lee
Fiona
F
Yull
Josiane E
JE
Eid
D000293:Adolescent; D000328:Adult; D000818:Animals; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D055786:Gene Knockout Techniques; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism*; D011774:Pyrvinium Compounds / Q000494:pharmacology; D012513:Sarcoma, Experimental; D013584:Sarcoma, Synovial / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays; D055815:Young Adult
D015514:Oncogene Proteins, Fusion; D011774:Pyrvinium Compounds; C116512:SYT-SSX fusion protein; C024631:pyrvinium