TBX3 in Combination with c-Myc and Nucleolin as Multiple Markers for the Early Detection of Sarcomas
Prof Sharon Prince
Title of the project
TBX3 in combination with c-Myc and Nucleolin as multiple markers for the early detection of sarcomas.
Sarcomas are highly diverse mesenchymal malignancies of the bone, cartilage, muscle, peripheral nerves, and adipose or fibrous connective tissues. They represent a complex group of neoplasms whose clinical management is severely challenged due to their heterogeneity, aggressive nature and their insensitivity to current treatments. They represent some of the most aggressive cancers in children and young adults and while the incidence rates for sarcomas in Africa remain uncertain, there is a widely held view that they are common in black African children. Indeed, the HIV related Kaposi Sarcoma remains a significant contributor to morbidity and mortality in sub-Saharan Africa and it was reported that soft tissue sarcomas make up as much as 11.3% of all childhood cancers. It is generally accepted that the burden of sarcomas can be reduced if their cells of origin are identified and if we have multiple and effective early diagnostic markers which requires an understanding of the molecular mechanisms underlying the pathogenesis of individual sarcoma subtypes.
Although the ultimate cells of origin of sarcoma subtypes remain unclear, there is increasing evidence that they arise de novo from mesenchymal pluripotent stem cells. We recently reported that the developmentally important transcription factor TBX3 is upregulated in several soft tissue and bone sarcoma cell lines and patient-derived sarcoma tissues. We explored the significance of this overexpression using TBX3 knockdown and overexpression cell culture and mouse models and demonstrated that TBX3 promotes proliferation, tumour formation, migration and invasion of chondrosarcoma, liposarcoma and rhabdomyosarcoma cells. Furthermore, we showed that TBX3 is upregulated by the oncogenic c-Myc and that it binds to and co-operates with nucleolin to drive proliferation and migration of the above-mentioned sarcomas. We therefore hypothesize that (1) TBX3 in combination with c-Myc and nucleolin may be important early differential biomarkers of a subset of sarcomas and (2) TBX3 alone can drive the transformation of mesenchymal stromal/stem cells into these sarcoma types. This study proposes to test these hypotheses because results emanating from it will have important implications for the early diagnosis of mesenchyme-derived cancers which are highly aggressive and mostly affect children.