Ji Ming Wang, M.D., Ph.D.
Leukocyte infiltration is a hallmark of inflammation and cancer progression. Leukocyte infiltration is mediated by G-protein coupled receptors (GPCRs) recognizing pathogen-, tumor- and host-derived chemoattractants. My laboratory focuses on the mechanisms of GPCRs regulating leukocyte trafficking in infection, inflammation, immune responses and cancer. We have revealed a critical role of GPCRs sequentially expressed by leukocytes in relaying chemotactic signals to guide cell recruitment in host responses. My laboratory has also discovered active participation of GPCRs in human gliblastoma progression as well as in colon mucosal homeostasis, inflammation and anti-tumor defense.
The Role of Chemoattractants and Receptors in Inflammation, Immune Responses and Tumor Progression
Chemoattractant receptors are seven-transmembrane, G-protein coupled receptors (GPCRs), which, by recognizing exogenous or host derived chemotactic factors, mediate many key pathophysiological processes including leukocyte trafficking, inflammation, immune responses, angiogenesis, wound healing and hematopoiesis. Some chemoattractant GPCRs also participate in tumor progression by recruiting immune cell infiltration into the tumor, promoting tumor angiogenesis, and mediating tumor invasion and metastasis.
Dr. Wang's laboratory is particularly interested in a group of chemoattractant GPCRs named FPRs, which were initially indentified in phagocytic leukocytes based on recognition of bacterial chemotactic formylated peptides. Subsequently, a number of novel host-derived chemoattractant agonists for FPRs have been identified and the receptors are detected in various cell types, suggesting a broader role of these receptors in vivo.
In studies of the role of FPRs in inflammation and tumor progression, Dr. Wang's laboratory found that one member of the FPR family, FPR1 (initially termed FPR), was more highly expressed by human grade IV glioblastoma multiforme (GBM), a most deadly tumor type in human brain.
Experiments with GBM cell lines revealed that FPR1 in tumor cells was activated by agonist(s) released by necrotic GBM cells. FPR1 then transactivates the receptor for epidermal growth factor (EGFR) and the two receptors cooperate to exacerbate the malignant behavior of GBM cells. Depletion of both receptors from GBM cells reduced their capacity to form tumors in animal models. Dr. Wang's laboratory is now characterizing the nature of the FPR1 agonists released by necrotic GBM cells and pursues the possibility of targeting FPR1 and its tumor-derived agonists as potential novel GBM therapies.
In addition to FPR1, Dr. Wang's laboratory also studies the role of another FPR family member, FPR2 (originally named FPRL1) in diseases. FPR2 not only recognizes bacterial chemotactic formylated peptides, but also interacts with a great number of host-derived agonists associated with inflammation, immune responses and tumors.
Dr. Wang's laboratory has developed mice deficient in the human FPR2 counterpart, mFPR2. These mice exhibited severely reduced innate and adaptive immune responses in an allergic airway inflammation disease model. These defects in mFPR2 deficient mice were associated with impaired trafficking of antigen presenting dendritic cells into the inflamed tissue and draining lymph nodes.
These findings suggest the possibility of profound influence of mFPR2 in dendritic cell differentiation and maturation in vivo, which are critical for host responses in inflammation, immune responses and resistance to cancer development. Dr. Wang's laboratory is actively studying these issues by using various genetic engineering approaches in order to obtain a better understanding of disease mechanisms and to indentify therapeutic targets.
Selected Key Publications
Identification of RANTES receptors on human monocytic cells: competition for binding and desensitization by homologous chemotactic cytokines.J. Exp. Med. 177: 699-705, 1993. [ Journal Article ]
A seven-transmembrane, G protein-coupled receptor, FPRL1, mediates the chemotactic activity of serum amyloid A for human phagocytic cells.J. Exp. Med. 189: 395-402, 1999. [ Journal Article ]
- J. Natl. Cancer Inst. 97: 823-35, 2005. [ Journal Article ]
- Nature. 498: 371-5, 2013. [ Journal Article ]
Formylpeptide receptor-2 contributes to colonic epithelial homeostasis, inflammation, and tumorigenesis.J. Clin. Invest. 123: 1694-704, 2013. [ Journal Article ]
Dr. Wang received his M.D. from Shanghai 2nd Medical University and his Ph.D. from Lombardy Regional School of Professional Education in Pharmacology, Milan, Italy.
|Keqiang Chen, Ph.D.||Staff Scientist|
|Wang-Hua Gong||Research Associate III (Leidos)|
|Jiaqiang Huang Ph.D.||Research Collaborator|
|Stacey Krepel BSc.||Postbaccalaureate Fellow (CRTA)|
|Weiwei Liang||Special Volunteer|
|Meihua Zhang||Special Volunteer|