TAK1 signaling in Rhabdomyosarcoma tumorigenesis and growth

Abstract Rhabdomyosarcoma (RMS) is a type of malignant (cancerous) sarcoma that typically arises in or near muscle beds and shows features of myogenic differentiation, such as expression of myogenic regulatory factors and muscle structural proteins. However, RMS cells continue to proliferate and do not undergo terminal differentiation. Transforming growth factor β-activated kinase 1 (TAK1) is a major signaling protein involved in the activation of various intracellular pathways. However, the role of TAK1 in RMS or any other sarcoma has not been investigated. Our preliminary results demonstrate that TAK1 is highly activated in both embryonal RMS and alveolar RMS cells and human RMS samples. Inhibition of TAK1 using genetic or pharmacological approaches represses epithelial-mesenchymal transition (EMT) and cancer stem cell phenotypes in cell culture and in vivo models of RMS. Inhibition of TAK1 also improves differentiation of various RMS subtypes cell lines into myogenic lineage and inhibits tumor formation by promoting myogenic differentiation in xenograft. In addition, TAK1 forms a complex with intracellular myostatin protein in RMS cells. However, the cellular and molecular mechanisms by which TAK1 promotes tumorigenesis and impairs differentiation of RMS remain entirely unknown. Furthermore, therapeutic potential of inhibition of TAK1 in RMS has not yet been examined using preclinical animal models. Based on our preliminary studies, we hypothesize that aberrant activation of TAK1 causes tumorigenesis and growth of RMS and inhibition of TAK1 can be a potential therapeutic approach for RMS. In this project, we will investigate the molecular mechanisms through which TAK1 induces tumorigenesis and inhibits myogenic differentiation in RMS (Aim I); investigate the signaling mechanisms through which TAK1 causes CSC enrichment and inhibits differentiation of RMS (Aim II); and examine the therapeutic potential of inhibition of TAK1 on xenografts and patient-derived xenograft (PDX) models of RMS (Aim III). Our study aims to identify a novel therapeutic target that plays a critical role in the induction of tumorigenesis and suppression of myogenic differentiation in RMS. Our unique strategy to target tumor progenitor cells and differentiation of RMS through modulating TAK1 will open new avenues to treat RMS.