Division of Hematology/Oncology
600 Moye Blvd., Brody 3E127
Greenville, NC 27834
Cancer biology and inflammation are the main research interests in our laboratory. Particularly, we study how tumor microenvironments regulate the progression, metastasis and therapeutic response of cancer. In the tumor, cancer cells closely interact with blood vessels, immune cells, and other stromal cells in a unique microenvironment. Due to defective blood flow and increased glycolytic metabolism of cancer cells (Warburg effect), tumor microenvironments are characterized by acidosis and hypoxia that play important roles in regulating cancer progression and response to therapeutics. Additionally, acidic and hypoxic microenvironments also frequently exist in inflammation, ischemia, and many other pathological conditions. However, the mechanisms by which cells respond to acidosis in the microenvironment are not well understood.
We focus on a family of pH-sensing G protein-coupled receptors (GPCRs) that are activated by acidic extracellular pH. Our goal is to understand how the acidic microenvironment regulates the behavior of cancer cells, blood vessels, and immune cells at the molecular level. Currently we are pursuing several research directions including: (1) How acidosis/GPCR signaling regulates tumor growth, metastasis, response to therapeutics, and cancer cell metabolism; (2) How acidosis/GPCR signaling regulates inflammation and immune cell function; (3) Evaluate therapeutic potentials of the pH-sensing GPCR modulators. These studies aim to identify new targets and approaches for the treatment and prevention of cancer, inflammation and other acidosis-related diseases.In summary, the long-term goal of our research is to understand the molecular determinants of tumorigenesis by delineating the complex interaction between cancer cells and the tumor microenvironment. As illustrated by the “seed and soil” theory, both the “seed” (cancer cells) and the “soil” (microenvironment including stromal cells) are important for tumor development. Thus, targeting both the “seed” and the “soil” can help devise more effective approaches for cancer therapy and prevention
Edward J. Sanderlin, Nancy R. Leffler, Kvin Lertpiriyapong, Qi Cai, Heng Hong, Vasudevan Bakthavatchalu, James G. Fox, Joani Zary Oswald, Calvin R. Justus, Elizabeth A. Krewson, Dorcas O’Rourke, Li V. Yang (2017). GPR4 deficiency alleviates intestinal inflammation in a mouse model of acute experimental colitis. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease 1863: 569-584. DOI: dx.doi.org/10.1016/j.bbadis.2016.12.005.
James A. McCubrey, Dariusz Rakus, Agnieszka Gizak, Linda S. Steelman, Steve L. Abrams, Kvin Lertpiriyapong, Timothy L. Fitzgerald, Li V. Yang, Giuseppe Montalto, Melchiorre Cervello, Massimo Libra, Ferdinando Nicoletti, Aurora Scalisi, Francesco Torino, Concettina Fenga, Luca M. Neri, Sandra Marmiroli, Lucio Cocco, Alberto M. Martelli (2016). Effects of Mutations in Wnt/β-Catenin, Hedgehog, Notch and PI3K Pathways on GSK-3 Activity—Diverse Effects on Cell Growth, Metabolism and Cancer. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research 1863: 2942-2976. DOI: 10.1016/j.bbamcr.2016.09.004.
Wenhuan Jiang, Jun Qing Lu, Li V. Yang, Yu Sa, Yuanming Feng, Junhua Ding, Xin-Hua Hu (2016). Comparison study of distinguishing cancerous and normal prostate epithelial cells by confocal and polarization diffraction imaging. Journal of Biomedical Optics 21(7): 071102. DOI: 10.1117/1.JBO.21.7.071102.
Jellert T. Gaublomme, Nir Yosef, Youjin Lee, Rona S. Gertner, Li V. Yang, Chuan Wu, Pier Paolo Pandolfi, Tak Mak, Rahul Satija, Alex K. Shalek, Vijay K. Kuchroo, Hongkun Park, Aviv Regev (2015). Single-cell genomics unveils critical regulators of Th17 cell pathogenicity. Cell 163: 1400-1412. DOI: 10.1016/j.cell.2015.11.009.
Calvin R. Justus, Edward J. Sanderlin, Li V. Yang (2015). Molecular connections between cancer cell metabolism and the tumor microenvironment. International Journal of Molecular Sciences 16(5): 11055-11086. DOI: 10.3390/ijms160511055.
Calvin R. Justus, Li V. Yang (2015). GPR4 decreases B16F10 melanoma cell spreading and regulates focal adhesion dynamics through the G13/Rho signaling pathway. Experimental Cell Research 334: 100-113. DOI: 10.1016/j.yexcr.2015.03.022.
Edward J. Sanderlin, Calvin R. Justus, Elizabeth A. Krewson, Li V. Yang (2015). Emerging roles for the pH-sensing G protein-coupled receptors in response to acidotic stress. Cell Health and Cytoskeleton 7: 99-109. DOI: 10.2147/CHC.S60508.
Lixue Dong, Zhigang Li, Li V. Yang (2014). Function and signaling of the pH-sensing G protein-coupled receptors in physiology and diseases. Chapter 4 in "Molecular Genetics of Dysregulated pH Homeostasis", edited by Dr. Jen-Tsan Ashley Chi, Springer (New York), ISBN 978-1-4939-1682-5, page 45-65. DOI: 10.1007/978-1-4939-1683-2_4.
Yuanming Feng, Ning Zhang, Kenneth M. Jacobs, Wenhuan Jiang, Li V. Yang, Zhigang Li, Jun Q. Lu, Xin-Hua Hu (2014). Polarization imaging and classification of Jurkat T and Ramos B cells using a flow cytometer. Cytometry Part A 85(9): 817-826. DOI: 10.1002/cyto.a.22504.
Xiaofei Chen, Joshua Corbin, Greg Tipton, Li V. Yang, Adam S. Asch, Maria J. Ruiz-Echevarria (2014). The TMEFF2 tumor suppressor modulates integrin expression, RhoA activation and invasion of prostate cancer cells. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research 1843(6): 1216-1224. DOI: 10.1016/j.bbamcr.2014.03.005.
Calvin R. Justus, Nancy R. Leffler, Maria J. Ruiz-Echevarria, Li V. Yang (2014). In vitro cell migration and invasion assays. Journal of Visualized Experiments 88, e51046. DOI: 10.3791/51046.
Calvin R. Justus, Lixue Dong, Li V. Yang (2013). Acidic tumor microenvironment and pH-sensing G protein-coupled receptors. Frontiers in Physiology 4:354. DOI: 10.3389/fphys.2013.00354.
Zhigang Li, Lixue Dong, Eric Dean, Li V. Yang (2013). Acidosis decreases c-Myc oncogene expression in human lymphoma cells: a role for the proton-sensing G protein-coupled receptor TDAG8. International Journal of Molecular Sciences 14(10): 20236-20255. DOI: 10.3390/ijms141020236.
Jun Zhang, Yuanming Feng, Marina S. Moran, Jun Q. Lu, Li V. Yang, Yu Sa, Ning Zhang, Lixue Dong, Xin-Hua Hu (2013). Analysis of cellular objects through diffraction images acquired by flow cytometry. Optics Express 21(21): 24819-24828.
Lixue Dong, Zhigang Li, Nancy R. Leffler, Adam S. Asch, Jen-Tsan Chi, Li V. Yang (2013). Acidosis activation of the proton-sensing GPR4 receptor stimulates vascular endothelial cell inflammatory responses revealed by transcriptome analysis. PLOS ONE 8: e61991. DOI: 10.1371/journal.pone.0061991.
Ying Zhang, Yuanming Feng, Calvin R. Justus, Wenhuan Jiang, Zhigang Li, Jun Q. Lu, R. Scott Brock, Matthew K. McPeek, Douglas A. Weidner, Li V. Yang, Xin-Hua Hu (2012). Comparative study of 3D morphology and functions on genetically engineered mouse melanoma cells. Integrative Biology 4: 1428-1436.
Li V. Yang, Reid D. Castellone, Lixue Dong (2012). Targeting tumor microenvironments for cancer prevention and therapy. Chapter 1 in “Cancer Prevention - From Mechanisms to Translational Benefits”, edited by Dr. Alexandros Georgakilas, InTech, ISBN 978-953-51-0547-3, page 3-40. DOI: 10.5772/28692.
Aishe Chen, Lixue Dong, Nancy R. Leffler, Adam S. Asch, Owen N. Witte, Li V. Yang (2011). Activation of GPR4 by acidosis increases endothelial cell adhesion through the cAMP/Epac pathway. PLOS ONE 6: e27586. DOI: 10.1371/journal.pone.0027586.
Reid D. Castellone, Nancy R. Leffler, Lixue Dong, Li V. Yang (2011). Inhibition of tumor cell migration and metastasis by the proton-sensing GPR4 receptor. Cancer Letters 312:197-208.
Ke Dong, Yuanming Feng, Kenneth M. Jacobs, Jun Q. Lu, R. Scott Brock, Li V. Yang, Fred E. Bertrand, May A. Farwell, Xin-Hua Hu (2011). Label-free classification of cultured cells through diffraction imaging. Biomedical Optics Express 2:1717-1726.
Xuming Sun, Li V. Yang, Brian C. Tiegs, Lois J. Arend, Dennis W. McGraw, Raymond B. Penn, Snezana Petrovic (2010). Deletion of the pH sensor GPR4 decreases renal acid excretion. Journal of the American Society of Nephrology 21:1745-1755.
Kenneth M. Jacobs, Li V. Yang, Junhua Ding, Andrew E. Ekpenyong, Reid Castellone, Jun Q. Lu, Xin-Hua Hu (2009). Diffraction imaging of spheres and melanoma cells with a microscope objective. Journal of Biophotonics 2: 521-527.
Christoph Peter, Michaela Waibel, Caius G. Radu, Li V. Yang, Owen N. Witte, Klaus Schulze-Osthoff, Sebastian Wesselborg, Kirsten Lauber (2008). Migration to apoptotic “find-me” signals is mediated via the phagocyte receptor G2A. Journal of Biological Chemistry 283: 5296-5305.
Li V. Yang, Caius G. Radu, Meenakshi Roy, Sunyoung Lee, Jami McLaughlin, Michael A. Teitell, M. Luisa Iruela-Arispe, Owen N. Witte (2007). Vascular abnormalities in mice deficient for the G protein-coupled receptor GPR4 that functions as a pH sensor. Molecular and Cellular Biology 27: 1334-1347.
Yang LV, Wan J, Ge Y, Fu Z, Kim SY, Fujiwara Y, Taub JW, Matherly LH, Eliason J, Li L (2006). The GATA site-dependent hemogen promoter is transcriptionally regulated by GATA1 in hematopoietic and leukemia cells. Leukemia 20: 417-425.
Caius G. Radu, Donghui Cheng, Amar Nijagal, Mireille Riedinger, Jami McLaughlin, Li V. Yang, James Johnson, Owen N. Witte (2006). Normal immune development and glucocorticoid-induced thymocyte apoptosis in mice deficient for the T-cell death-associated gene 8 receptor. Molecular and Cellular Biology 26: 668-677.
Li Wang, Caius G. Radu, Li V. Yang, Laurent A. Bentolila, Mireille Riedinger, Owen N. Witte (2005). Lysophosphatidylcholine-induced surface redistribution regulates signaling of the murine G protein-coupled receptor G2A. Molecular Biology of the Cell16: 2234-2247.
Li V. Yang, Caius G. Radu, Li Wang, Mireille Riedinger, Owen N. Witte (2005). Gi-independent macrophage chemotaxis to lysophosphatidylcholine via the immunoregulatory GPCR G2A. Blood 105: 1127-1134.
Caius G. Radu, Li V. Yang, Mireille Riedinger, Matthew Au, Owen N. Witte (2004). T cell chemotaxis to lysophosphatidylcholine through the G2A receptor. Proceedings of the National Academy of Sciences (PNAS) 101: 245-250.
Li V. Yang, Henry H. Heng, Junmei Wan, Cherie M. Southwood, Alexander Gow, Li Li (2003). Alternative promoters and polyadenylation regulate tissue-specific expression of Hemogen isoforms during hematopoiesis and spermatogenesis. Developmental Dynamics 228: 606-616.
Jay Uhler, James Garbern, Li Yang, John Kamholz, Dervla M. Mellerick (2002). NK6, a novel Drosophila homeobox gene regulated by vnd. Mechanisms of Development 116:105-116.
Li V. Yang, Rhonda H. Nicholson, Joseph Kaplan, Anne Galy, Li Li (2001). Hemogen is a novel nuclear factor specifically expressed in mouse hematopoietic development and its human homologue EDAG maps to chromosome 9q22, a region containing breakpoints of hematological neoplasms. Mechanisms of Development 104:105-111.