We propose to test the hypothesis that when ligand binds chemokine receptors, a """"""""dynamic chemosynapse"""""""" forms, comprised of receptor and adaptor proteins that serve to enable polarization, activation, amplification, and oscillation of small GTPases and kinases involved in organization of the actin cytoskeleton, and chemotaxis. Moreover, we propose that interference of chemokine receptor association with these adaptors will ablate CXCR2- and CXCR4-mediated chemotaxis, intravasation, extravasation, and metastasis. There are three specific aims. I) To test the hypothesis that a major role of AP-2 in mediating CXCR2/CXCR4 chemotaxis and metastasis is to orchestrate polarization and amplification of intracellular signals. We will separately interfere with AP-2 mediated receptor trafficking versus polarization of intracellular signals to distinguish the importance of these two functions of AP-2 in CXCR2/CXCR4 mediated chemotaxis and metastasis. 2) To characterize the role of IQGAP1 and VASP in linking the CXCR2 and CXCR4 chemosynapse to the actin cytoskeleton. We will characterize the interacting domains of IQGAP1 and VASP with CXCR2 and CXCR4 and determine the effects of altering these interactions on the functional responses to chemokine (including extravasation, intravasation, metastasis) of leukocytes, endothelial cells and breast cancer cells. 3) To test the hypothesis that Src-family kinase activation at the CXCR2 and CXCR4 `chemosynapse'drives chemotaxis that is Dock2 dependent and largely PI3K independent. We will determine the role of the Src-p130Cas-CrkL-Dock2 pathway in PI3K independent CXC2/CXCR4 chemotaxis. We will study these processes in dHL-60, dU937, HMEC-1 CXCR2 expressing cells and in the breast cancer cell lines naturally expressing CXCR4 (highly invasive MDA-MB-231, DU4475, BT-549 and non-invasive MCF-7, MDA-MB- 453 and MCF-10A cells). Microfluidic devices and real time intravital microscopy using 2 photon imaging will be used to track chemotaxis in vitro and intravasation/extravasation /metastasis in vivo, respectively. Characterization of the functional significance of this interaction between chemokine receptors and adaptor proteins that comprise the chemosynapse will unveil important new therapeutic targets for the treatment of malignancies. Characterization of the mechanism for PI3K independent chemotaxis will provide valuable information for design of therapies for sepsis, arthritis, and metastasis.
This study aims to test the hypothesis that receptors involved in regulating the motility of immune cells and tumor cells must interact with a number of proteins in the cytoplasm of the cell to stimulate proper organization of the cytoskeleton. In this study we propose to disrupt these protein/protein interactions to develop a new way of blocking tumor cell metastasis and chronic inflammation. We also will interrupt specific intracellular signals initiated by these protein/protein interactions to point the way to new targets for drug therapy for chronic inflammation and metastasis.
|Yang, Jinming; Kumar, Amrendra; Vilgelm, Anna E et al. (2018) Loss of CXCR4 in Myeloid Cells Enhances Antitumor Immunity and Reduces Melanoma Growth through NK Cell and FASL Mechanisms. Cancer Immunol Res 6:1186-1198|
|Pellom Jr, Samuel T; Dudimah, Duafalia F; Thounaojam, Menaka C et al. (2017) Bortezomib augments lymphocyte stimulatory cytokine signaling in the tumor microenvironment to sustain CD8+T cell antitumor function. Oncotarget 8:8604-8621|
|Lavender, Nicole; Yang, Jinming; Chen, Sheau-Chiann et al. (2017) The Yin/Yan of CCL2: a minor role in neutrophil anti-tumor activity in vitro but a major role on the outgrowth of metastatic breast cancer lesions in the lung in vivo. BMC Cancer 17:88|
|Sai, Jiqing; Owens, Philip; Novitskiy, Sergey V et al. (2017) PI3K Inhibition Reduces Mammary Tumor Growth and Facilitates Antitumor Immunity and Anti-PD1 Responses. Clin Cancer Res 23:3371-3384|
|Duvall-Noelle, N; Karwandyar, A; Richmond, A et al. (2016) LASP-1: a nuclear hub for the UHRF1-DNMT1-G9a-Snail1 complex. Oncogene 35:1122-33|
|Richmond, Ann; Yang, Jinming (2016) The role of NF-kB in modulating antitumor immunity. Oncoimmunology 5:e1005522|
|Vilgelm, Anna E; Johnson, C Andrew; Prasad, Nripesh et al. (2016) Connecting the Dots: Therapy-Induced Senescence and a Tumor-Suppressive Immune Microenvironment. J Natl Cancer Inst 108:djv406|
|Sobolik, Tammy; Su, Ying-Jun; Ashby, Will et al. (2016) Development of novel murine mammary imaging windows to examine wound healing effects on leukocyte trafficking in mammary tumors with intravital imaging. Intravital 5:e1125562|
|Saxon, Jamie A; Sherrill, Taylor P; Polosukhin, Vasiliy V et al. (2016) Epithelial NF-?B signaling promotes EGFR-driven lung carcinogenesis via macrophage recruitment. Oncoimmunology 5:e1168549|
|Johnson, Douglas B; Estrada, Monica V; Salgado, Roberto et al. (2016) Melanoma-specific MHC-II expression represents a tumour-autonomous phenotype and predicts response to anti-PD-1/PD-L1 therapy. Nat Commun 7:10582|
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