Hong Du, PhD
Professor of Pathology & Laboratory Medicine
B.Sc., Wuhan University, Virology, Wuhan, China
Ph.D., City University of New York, Biochemistry, New York, NY
Post Doctoral., The Rockefeller University, Molecular Biology and Biochemistry, New York, NY
1. Ding, X., Zhang, W., Zhao, T., Du, H., and Yan, C. (2017) Rab7 GTPase controls lipid metabolic signaling in myeloid-derived suppressor cells. Oncotarget. In press.
2. Du, H., Ding, X., and Yan, C (2017) Metabolic reprogramming of myeloid-derived suppressive cells. Oncoscience. In press.
3. Zhao, T., Du, H., Blum J. S., and Yan, C. (2016) Lysosomal acid lipase is involved in mesenchyme stem cells’ stimulation of tumor growth and metastasis. Oncotarget. 7(38):61121-61135. doi: 10.18632/oncotarget.11244. PMID: 27531897
4. Grumet, L., Eichmann, T.O., Taschler, U., Zierler, K. A., Leopold, C., Moustafa, T., Radovic, B., Romauch, M., Yan, C., Du, H., Haemmerle, G., Zechner, R., Fickert, P., Kratky, D., Zimmermann, R., and Lass, A. (2016) Lysosomal acid lipase hydrolyzes retinyl ester and affects retinoid turnover. J Biol Chem. 291(34):17977-87. doi: 10.1074/jbc.M116.724054.
5. Radovic, B., Vujic, N., Leopold, C., Schlager, S., Goeritzer, M., Jay V. Patankar, J.V., Kolb, D., Reindl, J., Wegscheider, M., Birner-Grünberger, R., Schittmayer-Schantl, M., Groschner, L., Magnes, C., Diwoky, C., Sasa Frank, S., Steyrer, E., Zimmermann, R., Graier, W., Du, H. and Kratky, D. (2016) Hepatic regulation of increased insulin sensitivity in LAL-deficient mice. Diabetologia. 59:1743-52. doi: 10.1007/s00125-016-3968-6. Epub 2016 May 6.
6. Zhao, T., Ding , X., Du, H., and Yan, C. (2016) Lung Epithelial Cell-Specific Expression of Human Lysosome Acid Lipase Corrects Lung Inflammation and Tumor Metastasis in lal−/− Mice. Am J Pathol. 186(8):2183-92. doi: 10.1016/j.ajpath.2016.04.014. PMID: 27461363
7. Kumar, V., Cheng, P. Y., Condamine, T., McCaffrey, J.C., Hockstein, N., Witt, R., Masters, G., Bauer, T., Skrzypczynska, K., Weiss, A., Du, H., Yan C., and Gabrilovich, D.I. (2016) CD45 phosphotase regulates the fate of myeloid cells in tumor microenvironment by inhibiting STAT3 activity” Immunity 44(2):303-15. doi: 10.1016/j.immuni.2016.01.014.
8. Zhao, T., Du, H., Blum J. S., and Yan, C (2016) Critical Role of PPARγ in Myeloid-Derived Suppressor Cell-Stimulated Cancer Cell Proliferation and Metastasis. Oncotarget. 12;7(2):1529-43. doi: 10.18632/oncotarget.6414
9. Du, H., Zhao, T., Ding, X., and Yan, C. (2015) Hepatocyte-specific expression of human lysosomal acid lipase corrects liver inflammation and tumor metastasis in lal-/- mice. Am J Pathol. 185:2379-2389.
10. Zhao, T., Du, H., Ding, X., Walls, K., and Yan, C. (2015): Activation of mTOR Pathway in Myeloid-derived Suppressor Cells Stimulates Cancer Cell Proliferation and Metastasis in lal-/- Mice. Oncogene. 34:1938-48. Highlighted by Immune Regulation News 6.20.
11. Yan, C., Zhao, T. and Du, H. (2015) Lysosomal acid lipase in cancer. Editorial. Oncoscience, Invited Review. 2 (9):727-728
12. Ding, X., Wu, L., Yan, C. and Du, H. (2015): Establishment of lal-/- Myeloid Lineage Cell Line That Resembles Myeloid-derived Suppressive Cells. PLoS ONE. doi: 10.1371/journal.pone.0121001.
13. Huang, S. C., Everts, B., Ivanova, Y., O’Sullivan, D., Nascimento, M., Smith, A. M., Beatty, W., Love-Gregory, L., Lam, W. Y., O’Neill, C. M., Yan, C., Du, H., Abumrad, N. A., Urban, J. F., Artyomov, M., Pearce, E. L., Pearce, E. J. (2014) Cell-intrinsic lysosomal lipolysis is essential for macrophage alternative activation. Nature Immunology, 15:846-55.
14. Zhao, T., Ding, X., Du, H., and Yan, C. (2014): Myeloid-derived Suppressor Cells Are Involved in Lysosomal Acid Lipase Deficiency-Induced Endothelial Cell Dysfunction. J Immunol. 193:1942-53.
15. Sun, Y., Xu, Y. H., Du, H., Quinn, B., Liou, B., Stanton, L., Inskeep, V., Ran, H., Phillip Jakubowitz, P., Grilliot. N. and Grabowski, G.A. (2014) Reversal of advanced disease in lysosomal acid lipase deficient mice: a model for lysosomal acid lipase deficiency diseases. Molecular Genetics and Metabolism. 112:229-41.
16. Ferreira, A. E., Sisti, F., Sônego, F., Moreira, A. P., Filgueiras, L., Du, H., Cunha, F. Q., Alves-Filho, J. C., and Serezani, H. C. (2014) PPAR-g/IL-10 axis inhibits MyD88 expression and ameliorates murine polymicrobial sepsis. J Immunol. 192:2357-65.
17. Ding, X., Du, H., Yoder, M. C., and Yan, C. (2014) Critical Role of the mTOR pathway in Development and Function of Myeloid-derived Suppressor Cells in lal-/- Mice. Am J. Pathol 184:397-408.
18. Yan, C., and Du, H. (2014) Functional role of lysosomal acid lipase in myeloid derived suppressive cell development and homeostasis. World J Immunol, Invited Review. 4: 42-51.
19. Yan, C., Ding, X., Wu, L., Yu, M., Qu, P., and Du, H. (2013): Stat3 Downstream Gene Product Chitinase 3-Like 1 Is a Potential Biomarker of Inflammation-induced Lung Cancer in Multiple Mouse Lung Tumor Models and Humans. PLoS ONE. 22;8(4):e61984. PMID:23613996.
20. Yan, C., Qu, P., and Du, H. (2012) Myeloid-Specific Expression of Stat3C Results in Conversion of Bone Marrow Stem Cells into Alveolar Type II Epithelial Cells in the Lung. Sci China Life Sci. 55:576-590.
21. Wu, L.Y., Yan, C., Czader, M.B., Foreman, O., Blum J. S., Kapur, R., and Du, H. (2012) Inhibition of peroxisome proliferator-activated receptor-g in myeloid lineage cells induces systemic inflammation, immunosuppression and tumorigenesis. Blood. 119:115-126.
22. Yan, C., Ding, X. C., Dasgupta, N., Qu, P., Wu, L.Y., and Du, H. (2012) Gene profile of myeloid-derived suppressive cells from the bone marrow of lysosomal acid lipase knock-out mice. PLoS ONE 7 (2): e30701.
23. Wu, L.Y., Du, H., Li, Y., Qu, P., and Yan, C (2011) Signal Transducers and activators of the transcription3 promotes myeloid derived suppressor cell expansion and immune suppression during lung tumorigenesis. Am. J. Pathol. 179:2131-2141.
24. Qu, P., Yan, C., Blum, J. S., Kapur, R., and Du, H. (2011) Myeloid-specific expression of human lysosomal acid lipase corrects malformation and malfunction of myeloid-derived suppressive cells in lal-/- mice. J. Immunol. 187:3854-3866.
25. Bowden, K.L., Bilbey, N. J., Bilawchuk, L.M., Boadu, E., Ory, D.S., Hegele, R.A., Du, H., Chan, T., and Francis, G.A. (2011) Lysosomal acid lipase deficiency impairs regulation of ABCA1 and formation of high density lipoproteins in cholesteryl ester storage disease. J. Biol. Chem. 286:30624-30635.
26. Li, Y., Qu, P., Wu, L.Y., Li, B. L., Du, H., and Yan, C. (2011) Api6/AIM/Spa overexpression in alveolar type II epithelial cells induces spontaneous lung adenocarcinoma. Cancer Res. 71:5488-5499.
27. Wu, L.Y, Wang, G.X., Qu, P., Yan, C., and Du, H. (2011) Overexpression of Dominant Negative Peroxisome Proliferator-Activated Receptor-gamma (PPARg) in Alveolar Type II Epithelial Cells Causes Inflammation and T-Cell Suppression in the Lung. Am. J. Pathol. 178: 2191-2204.
28. Qu, P., Yan, C., and Du, H. (2011) Matrix Metalloproteinase 12 overexpression in myeloid lineage cells plays a key role in modulating hepatopoiesis, myelopoiesis, immune suppression and lung tumorigenesis. Blood. 117: 4476-4489.
Lysosomal acid lipase (LAL) hydrolyzes cholesteryl esters and triglycerides to generate free fatty acid and cholesterol in the lysosomes of various cells. The metabolites of the enzyme product serve as ligands for nuclear receptors and transcription factors that regulate gene expression, cell proliferation/differentiation and apoptosis. The physiological roles of LAL are evaluated using a gene targeted mouse model, LAL knock out mice (lal-/-) that created in my laboratory. Further characterization of lal-/- mice demonstrated additional roles of LAL in fat mobilization, insulin resistance, myeloid cell and T cell dysfunction, respiratory inflammation and remodeling. Our current research focuses on mechanisms that connect lipid metabolism disorder to the systemic inflammation that leads to multiple forms of pathogenic phenotypes in multiple organs.
1. Lipid metabolism controls tissue inflammation
We have demonstrated that LAL controlled lipid metabolic signaling is essential for development and homeostasis of hematopoietic and immune cell populations. During LAL deficiency, pathogenic myeloid-derived suppressive cells (MDSCs) were systemically expanded and possess strongly immunosuppressive function on T cell proliferation and function in vitro and in vivo. This lal-/- MDSCs expansion was initiated at the early stages of myeloid development in the bone marrow.
2. Direct stimulation of MDSCs on tumor proliferation
We are the first group demonstrating that lal-/- MDSCs can directly stimulate tumor cell proliferation in vitro, tumor growth and metastasis in vivo. This breakthrough is significant since MDSCs are normally considered as tumor promoting through their immunosuppressive function on T cells. Using three doxycycline inducible cell specific human LAL transgenic expression in lal-/- mouse models, we demonstrated the expression of human LAL in myeloid cells, or in hepatocytes, or in pulmonary type II epithelial cells can decreased MDSCs and reduced the tumor cell growth and metastasis of various tumor models.
3. Establishment of MDSCs-like cell lines
In order to facilitate characterization of biochemical and cellular mechanisms of MDSCs, we have established an “MDSC-like” cell line. By cross breeding of immortomouse® with wild type and lal-/- mice, we have established a wild type (HD1A) and a lal-/- (HD1B) myeloid cell lines. HD1B cells demonstrated many characteristics similar to lal-/- MDSCs. HD1B cells exhibited increased lysosomes around perinuclear areas, dysfunction of mitochondria skewing toward fission structure, damaged membrane potential, increased ROS production, and increased glycolytic metabolism. Similar to lal-/- MDSCs, the mTOR signal pathway in HD1B cells was overly activated. HD1B cells showed much stronger immunosuppression on CD4+ T cell proliferation and function in vitro, and enhanced cancer cells proliferation. These “MDSC-like” cell lines can be used as an alternative in vitro system to study MDSCs functions, including stimulation of cancer. Currently, these HD1A and HD1B MDSCs-like cell lines were exclusively licensed to Applied Biological Materials Inc. and commercially available to everyone in scientific field.
4. Establishment of inflammation-induced tumor animal models
In addition to inflammatory lal-/- mice, my laboratory has established multiple preclinical inflammation-induced lung and melanoma tumor mouse models (8 in total) to study mechanisms of cancer formation. Using Affymetrics gene microarray analysis, we identified a set of genes that are upregulated in lal-/- lung tissues and functionally relevant to the phenotypes of lal-/- lung. On the top of the list are matrix metalloproteinase-12 (MMP-12) (increased 100-fold) and apoptosis inhibitor 6 (Api6) (increased 67-fold). To further test if overexpression of MMP12 and Api6 are responsible for chronic inflammation and tumorigenesis, we have established cell specific (i.e. myeloid specific and lung epithelial specific) and doxycycline inducible transgenic mouse models to overexpress MMP12, Api6. These myeloid cell- or lung epithelial cell-specific mouse models induced spontaneous lung adenocarcinomas due to MDSCs expansion. These inflammation-induced animal models greatly accelerate elucidation of mechanisms by which inflammation induces lung cancer formation. They also facilitate identification of biomarkers for lung cancer diagnosis and prognosis.
5. Lung cancer biomarker identification
Lung cancer is one of the biggest public health challenges facing the United States and many other countries. Lung cancer is a difficult disease to detect in its early stages. In collaboration with Dr. Yan’s lab, we showed that Stat3 plays a critical role in inflammation-induced lung adenocarcinoma. This was further supported by human studies, in which the Stat3 expression level was up-regulated in human lung cancers. Affymetrix GeneChip microarray analysis was performed in the preclinical CCSP-rtTA/(tetO)7Stat3C lung tumor mouse model. We have successfully identified multiple Stat3 downstream secretory proteins as a panel that can be used for lung cancer diagnosis in the human sera.