Friday, April 26, 2024
4/26/2024
Project Summary/Abstract Rhabdomyosarcoma (RMS) is an aggressive pediatric soft tissue sarcoma characterized by the lack of myogenic differentiation. RMS is divided in two molecular categories: fusion positive (FP-RMS) carrying a balanced chromosomal translocation generating an oncogenic Pax3-FOXO1 or Pax7-FOXO1 protein, and fusion negative (FN-RMS) that does not include the fusion event. Current treatments for FN-RMS remain poor and the long-term event-free survival rate for FN-RMS metastatic patients is below 30%. TWIST2 transcription factor represses myogenesis by inhibiting MyoD function and knockdown of TWIST2 in FN-RMS is shown to inhibit tumor cell growth and enhance myogenic differentiation. To understand the mechanisms underlying TWIST2 function in FN-RMS, we sought to identify its direct transcriptional targets. Among them, we identified NT5E, encoding an ecto 5’-nucleotidase, as a direct target gene of TWIST2. NT5E’s main role is to convert adenosine- monophosphate to adenosine in the purinergic signaling pathway. NT5E has been shown to promote cancer progression, invasion and metastasis in human melanoma and breast cancer. However, it’s possible role in FN- RMS has not been explored. In this proposal, we hypothesize that NT5E contributes to FN-RMS tumor formation and progression through the activation of the purinergic signaling pathway. To test this hypothesis, we will investigate the contribution of NT5E expression to the pathogenesis of FN-RMS in vitro and in vivo. Then, we will delineate the molecular mechanism whereby NT5E promotes FN-RMS. Completion of this research plan will push the boundaries of our knowledge regarding the role of NT5E in FN-RMS pathogenesis with the ultimate goal of developing novel therapeutic strategies for FN-RMS.
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