Drosophila and mammalian models uncover a role for the myoblast fusion gene TANC1 in rhabdomyosarcoma

Abstract

Rhabdomyosarcoma (RMS) is a malignancy of muscle myoblasts, which fail to exit the cell cycle, resist terminal differentiation, and are blocked from fusing into syncytial skeletal muscle. In some patients, RMS is caused by a translocation that generates the fusion oncoprotein PAX-FOXO1, but the underlying RMS pathogenetic mechanisms that impede differentiation and promote neoplastic transformation remain unclear. Using a Drosophila model of PAX-FOXO1-mediated transformation, we show here that mutation in the myoblast fusion gene rolling pebbles (rols) dominantly suppresses PAX-FOXO1 lethality. Further analysis indicated that PAX-FOXO1 expression caused upregulation of rols, which suggests that Rols acts downstream of PAX-FOXO1. In mammalian myoblasts, gene silencing of Tanc1, an ortholog of rols, revealed that it is essential for myoblast fusion, but is dispensable for terminal differentiation. Misexpression of PAX-FOXO1 in myoblasts upregulated Tanc1 and blocked differentiation, whereas subsequent reduction of Tanc1 expression to native levels by RNAi restored both fusion and differentiation. Furthermore, decreasing human TANC1 gene expression caused RMS cancer cells to lose their neoplastic state, undergo fusion, and form differentiated syncytial muscle. Taken together, these findings identify misregulated myoblast fusion caused by ectopic TANC1 expression as a RMS neoplasia mechanism and suggest fusion molecules as candidates for targeted RMS therapy.

Probing for a deeper understanding of rhabdomyosarcoma: insights from complementary model systems

“…Exploiting this model, the rolling pebbles ( rols ) gene was isolated as a dominant PAX7–FOXO1 suppressor 106 . The rols gene encodes an adaptor molecule that is necessary for coordinating the intracellular machinery that drives myoblast cell–cell fusion in syncytial muscle 107–109 ( box 2 ).…”

“…Additionally, intracellular signalling proteins, such as β-catenin, creatine kinase, kindlin 2 and others, localize to the site of cell contact and regulate cytoskeletal rearrangement 154 . Studies in C2C12 cells have established that TANC1 (tetratricopeptide repeat, ankyrin repeat and coiled-coil containing protein 1; the mammalian Rols orthologue) is required for myoblast fusion 106 . Nephrin (the mammalian Sns orthologue) is required for the secondary fusion of myoblasts to form nascent myotubes 155 .…”

Alveolar rhabdomyosarcoma–associated PAX3-FOXO1 promotes tumorigenesis via Hippo pathway suppression

“…Although tumorigenesis is not detectable due to lethality, the misfused PAX3/7-FOXO1 myogenic cells act aggressively to infiltrate nonmuscle tissue (30). Forward genetic screening for PAX-FOXO1 enhancers/suppressors can then be used to identify novel PAX3/7-FOXO1 gene targets and effectors (30,31).…”

TransCONFIRM: Identification of a Genetic Signature of Response to Fulvestrant in Advanced Hormone Receptor–Positive Breast Cancer

“…In this gene set, upregulation of 27 genes was associated with poor PFS. These genes include genes that have known functions in the regulation of the ER transcriptional network (TFAP2C 18, 19 and SP1 20, 21 ), genes that have been shown to be related to breast cancer biology and clinical outcomes (TFAP2C, BMPR1A 22 , ARRDC3 23 , PPP2R3A 24 ) and genes not yet reported to be related to breast cancer but with functional roles in tumorigenesis, metastases and response to treatment in other cancer types and may also have molecular functions in breast cancer (ILF2 25 , ATP11B 26 , CSDA 27 , USP5 28 ,TANC1 29 , NOTCH2 30 , ADD3 31 and SEC23A 32 ). In addition, there are a number of genes in the gene set that do not have known roles in cancer biology (CCDC93, CPNE1, GLTP and TCEB3).…”