Rhabdomyosarcoma (RMS) is the most common sarcoma in children and very often infiltrates the bone marrow (BM). Our recently published data show that stromal derived factor-1 (SDF-1), which is secreted within the BM microenvironment, may play a crucial role in directing to the BM the RMS cells that express the receptor for SDF-1, CXCR4. To investigate the mechanisms operating in the metastasis of RMS and develop a new therapeutic approach to blocking the SDF-1-CXCR4 axis in RMS, we propose three aims.
Aim #1. To elucidate the molecular mechanisms of CXCR4 priming. Since we observed that scatter factor (SF) increases/primes the chemotactic response of CXCR4+ RMS cells to an SDF-1 gradient, we will focus on molecular mechanisms of crosstalk between the SDF-1-CXCR4 and SF-c-Met axes in RMS metastasis. We will investigate which SDF-1-mediated steps in metastasis are influenced by SF and, based on our preliminary data, we will test the hypothesis that SF by increasing inclusion of CXCR4 into membrane lipid rafts modulates the responsiveness of RMS cells to SDF-1 gradient.
Aim #2. To determine whether PAX genes regulate the expression of CXCR4. Since in RMS cell lines the expression of CXCR4 correlates with alveolar RMS and expression of the PAX3-FKHR and PAX7-FKHR genes, we will investigate whether PAX genes directly regulate CXCR4 expression in RMS cells. We will test whether CXCR4 expression in cells isolated from RMS patients also correlates with the alveolar type of RMS, and with PAX3- and PAX7-FKHR fusion and/or overexpression of PAX-3 and PAX-7 wild-type genes.
Aim # 3. To assess therapeutic strategies to block the metastatic behavior of RMS cells by targeting the SDF-1-CXCR4 axis. We noticed that radio-/chemotherapy induces SDF-1 secretion in various organs and creates a """"""""metastasis-permissive"""""""" environment. Thus we hypothesize that the SDF-1-CXCR4 axis may play a role in the spread of tumor cells that have escaped therapy. To control the spontaneous and radio-/chemotherapy-induced metastatic behavior of RMS cells in vivo, we will employ the newly synthesized small-molecular inhibitor of the CXCR4 receptor (TE14013) in a human RMS xenotransplant-immunodeficient mouse model. This work will be of relevance for designing strategies to block the SDF-1-CXCR4 axis to treat CXCR4-positive cancers.
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