β-catenin stabilization enhancesSS18-SSX2-driven synovial sarcomagenesis and blocks the mesenchymal to epithelial transition

Abstract

β-catenin is a master regulator in the cellular biology of development and neoplasia. Its dysregulation is implicated as a driver of colorectal carcinogenesis and the epithelial-mesenchymal transition in other cancers. Nuclear β-catenin staining is a poor prognostic sign in synovial sarcoma, the most common soft-tissue sarcoma in adolescents and young adults. We show through genetic experiments in a mouse model that expression of a stabilized form of β-catenin greatly enhances synovial sarcomagenesis. Stabilization of β-catenin enables a stem-cell phenotype in synovial sarcoma cells, specifically blocking epithelial differentiation and driving invasion. β-catenin achieves its reprogramming in part by upregulating transcription of TCF/LEF target genes. Even though synovial sarcoma is primarily a mesenchymal neoplasm, its progression towards a more aggressive and invasive phenotype parallels the epithelial-mesenchymal transition observed in epithelial cancers, where β-catenin's transcriptional contribution includes blocking epithelial differentiation.

BHX Inhibits the Wnt Signaling Pathway by Suppressing β-catenin Transcription in the Nucleus

“…In fact, the effects of BHX on the β-catenin protein expression levels were analyzed by immunofluorescence and Western blot, revealing that BHX decreased β-catenin levels in the cell nucleus. Down-regulating the nuclear β-catenin reduces the interaction of β-catenin and TCF/LEF, thereby suppressing the Wnt signaling pathway24. Herein, we also showed that the suppression of the nuclear translocation of β-catenin resulted in the down-regulated expression of cyclin D1 and c-myc, which were downstream oncogenes of the Wnt/β-catenin signaling pathway2526.…”

The Influential Role of BCL2 Family Members in Synovial Sarcomagenesis

“…MoJoSS was developed as previous described from a consented patient’s synovial sarcoma (19)]. Each was maintained in Dulbecco's modified eagle medium (DMEM) with 10% fetal bovine serum (FBS) and tested for mycoplasma using MycoAlert Plus (Lonza, Walkersville, MD) every 6 months.…”

Paracrine osteoprotegerin and β-catenin stabilization support synovial sarcomagenesis in periosteal cells

“…None of these mice developed tumors over the course of 1 year of monitoring ( Figure 3C). Of note, while the myogenic precursors defined by the postnatal Myf5Cre or Pax7Cre ERT2 lineages showed no significant origination potential for SS from expression of SS18-SSX2, prior data from localized, lineage-nonspecific induction of hSS1 or hSS2 expression had already demonstrated that some postnatal cells in both periosteal and muscle compartments retained origination potential (5,18).…”

“…We previously observed that TATCre injections into peritibial tissues consistently produced tumors in hSS2 Ctnnb1 ex3fl/WT mice, which express a floxed Ctnnb1 exon 3 (18). To test the tumor-originating capacity of other mesenchymal tissue compartments, we injected 8 hSS2 Ctnnb1 ex3fl/WT littermate mice with 10 μl TATCre to delete Ctnnb1 exon 3 in cells within the tibialis anterior muscle adjacent to bone, in the contralateral quadriceps muscle distant from bone, and in the subcutaneous tissue of the abdominal wall.…”

“…In previous experiments, we combined the expression of SS18-SSX2 with genetic stabilization of β-catenin (CTNNB1) in a localized tumorigenesis model induced by injection of AdCre virus or TATCre protein (18). We pursued these experiments because of the observation of APC-inactivating and CTNNB1-stabilizing mutations in a subset of human SSs, with a larger portion exhibiting deregulation of Wnt signaling (19)(20)(21)(22).…”