Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and adolescents, representing approximately 5% of all paediatric tumours. Histologically, RMS is classified in two main subtypes, alveolar (aRMS) and embryonal (eRMS), which differ in the clinical presentation, response to treatment and prognosis. aRMS shows poor prognosis and it is characterized by the presence of specific translocations, while eRMS does not present specific translocations and has better prognosis. Wnt signalling pathway is involved in numerous processes of the embryonic development and its deregulation is related to several cancer types. Unlike most tumours, Wnt pathway is inhibited in RMS and it has a tumour suppressive role, playing a leading role in the cellular differentiation process. Despite this, the underlying mechanism that leads Wnt pathway inactivation in RMS remains, to a large extent, unknown. In this thesis, the cause of the Wnt pathway inactivation and its implication in the oncogenesis of RMS are studied. Specifically, Dickkopf-1 (DKK-1) is pointed out as one of the key inhibitors of the Wnt pathway inhibition in RMS. For the first time, the effects of DKK-1 inhibition on the reduction of cellular proliferation and the induction of myogenic differentiation in RMS are determined. Preliminary results suggest a possible implication of DKK-1 in the metastasis implantation process. DKK-1 genetic inhibition and pharmacological inhibition using the commercial inhibitor WAY-262611 have been approached to determine the role of DKK1 in the oncogenesis of RMS. Interestingly, this work describes the correlation between DKK-1 expression and worse prognosis of RMS patients. In summary, this thesis describes the oncogenic role of DKK-1 in RMS, pointing it as a possible therapeutic target for the development of new therapeutic alternatives for this illness.
|Date of Award||19 Jun 2019|
|Supervisor||Anna Maria Bassols Teixido (Tutor), Maria Soledad Angeles Gallego Melcon (Director) & Josep Roma Castanyer (Director)|