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    Research Grants Awarded

    Breast tumor exosomal Jak3BP inhibits myeloid cell differentiation

    Study Section:
    Tumor Cell Biology III

    Scientific Abstract:
    The overall goal of this proposal is to identify the mechanisms underlying tumor exosome-mediated suppression of immature myeloid cell differentiation. Our preliminary data and others (1) indicate that pretreatment of BALB/c mice with exosomes produced by TS/A breast tumor cells results in more rapid tumor growth and earlier metastasis. We have identified a novel breast tumor exosomal protein (Jak3BP) that is capable of binding to Jak3 in the immature myeloid cells, resulting in the ubiquitination of Jak3. The results of siRNA Jak3BP knockout indicate that Jak3BP is required for ubiquitination of Jak3 in GM-CSF-stimulated CD11b+Gr-1+ myeloid cells and prevents their differentiation. Our recent data suggest that Jak3BP is packed in exosomes isolated from breast cancer patients but not healthy subjects. Our Aims are: (1) Using a mouse model, to determine if knockout of Jak3BP in implanted tumor cells is sufficient for prevention of tumor growth; (2) To determine whether human breast tumor exosomal Jak3BP plays a role in blocking differentiation of circulating CD33 (equivalent to mouse CD11b+)Gr1+ cells and whether this is associated with disease status; and (3) To identify and characterize the tumor exosomal E3 ligase complex that interacts with Jak3 and Jak3BP leading to Jak3 degradation. The data generated should elucidate the cellular and molecular basis for tumor exosome-mediated blockade of myeloid cell differentiation

    Lay Abstract:
    Tumors can promote their own growth by suppressing the immune response of the patient. It is now well established that tumors produce "exosomes" that can deliver proteins to host cells. We have shown that administration of exosomes purified from the supernatants of mouse breast tumor cell lines promotes the growth of implanted tumors and that this is associated with the accumulation of immature myeloid cells in the spleen, i.e., the exosomes prevent the development of mature, functioning lymphocytes. Our preliminary data indicate that the exosome protein that plays the primary role in these effects is Jak3 binding protein (Jak3BP), which degrades a key component of the myeloid cell differentiation signaling pathway, Jak3. Jak3BP had not been described prior to these studies of the mouse tumor exosomes. We hypothesize that this mechanism is associated with the ability of human breast tumors to suppress the immune response and will test this hypothesis using knock out of Jak3BP, analysis of the stability of Jak3BP in immature myeloid cells in the peripheral blood of patients with breast cancer, and analysis of the correlation of the levels of tumor exosomes containing Jak3BP in peripheral blood is correlated with poor outcome in human breast cancer. The study has the potential to indicate novel strategies that could prevent tumor-mediated immunosuppression and boost immunosurveillance, thus preventing establishment of metastatic tumors as well as the growth of primary tumors. It also may identify a potential marker for early detection.