The major focus of research in our laboratory is to study how cells perceive and respond to tissue microenvironments in cancer and other diseases such as inflammation and ischemia. Tumor is an abnormal organ-like structure in which cancer cells closely interact with blood vessels, immune cells, and stromal cells in a unique tissue microenvironment. Due to defective blood flow and increased glycolysis of cancer cells (Warburg effect), tumor microenvironments are characterized by hypoxia and acidosis that are important for cancer progression and response to chemo- and radio-therapies. Moreover, acidic tissue 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, immune cells, and stromal cells at the molecular level. Currently we are pursuing several research directions including: (1) How acidosis/GPCR signaling regulates tumor growth, metastasis, and response to chemo- and radio-therapies; (2) How acidosis/GPCR signaling regulates angiogenesis and the endothelium-immune cell interaction; (3) Through collaborations, we are using high-throughput chemical screening to identify potential small molecule modulators of the pH-sensing GPCRs. The studies have implications in cancer and other acidosis-related diseases such as inflammation, ischemia, and renal, respiratory and metabolic diseases.
Lixue Dong,Zhigang Li, Li V. Yang * (2014). Function and signaling of thepH-sensing G protein-coupled receptors in physiology and diseases. Book chapterin "Molecular Genetics of Dysregulated pH Homeostasis",edited by Dr. Jen-Tsan Ashley Chi, Springer Science+Business Media (New York),ISBN 978-1-4939-1682-5, page 45-65. doi: 10.1007/978-1-4939-1683-2_4.
YuanmingFeng, Ning Zhang, Kenneth M. Jacobs, Wenhuan Jiang, Li V. Yang, Zhigang Li,Jun Q. Lu, Xin-Hua Hu (2014). Polarization imaging and classification of JurkatT and Ramos B cells using a flow cytometer. Cytometry 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 integrinexpression, RhoA activation and invasion of prostate cancer cells. Biochimicaet Biophysica Acta 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 VisualizedExperiments 88, e51046. doi: 10.3791/51046.
Calvin R.Justus, Lixue Dong, Li V. Yang * (2013). Acidic tumor microenvironmentand pH-sensing G protein-coupled receptors. Frontiers in Physiology4:354. doi: 10.3389/fphys.2013.00354. (Invited review for the ResearchTopic "Acid-base sensing and regulation: molecular mechanisms and functionalimplications in health and disease")
Zhigang Li,Lixue Dong, Eric Dean, Li V. Yang * (2013). Acidosis decreases c-Myconcogene expression in human lymphoma cells: a role for the proton-sensing Gprotein-coupled receptor TDAG8. International Journal of MolecularSciences 14(10): 20236-20255.
Jun Zhang,Yuanming Feng, Marina S. Moran, Jun Q. Lu, Li V. Yang, Yu Sa, NingZhang, Lixue Dong, Xin-Hua Hu (2013). Analysis of cellular objects throughdiffraction images acquired by flow cytometry. Optics Express21(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 stimulatesvascular endothelial cell inflammatory responses revealed by transcriptomeanalysis. PLOS ONE 8(4): e61991. doi:10.1371/journal.pone.0061991.
Ying Zhang,Yuanming Feng, Calvin R. Justus, Wenhuan Jiang, Zhigang Li, Jun Q. Lu, R. ScottBrock, Matthew K. McPeek, Douglas A. Weidner, Li V. Yang *, Xin-Hua Hu *(2012). Comparative study of 3D morphology and functions on geneticallyengineered mouse melanoma cells. Integrative Biology 4:1428-1436.
Ying Zhang,Na Hu, Yan Wang, Chunmei Yang, Li Yang, Xin-Hua Hu, Yuanming Feng(2012). Stereological and laser scanning confocal microscopic analysis of3-dimensional morphology of melanoma cells. Acta Optica Sinica 32(9): 0917001.
Li V. Yang *, Reid D. Castellone, Lixue Dong(2012). Targeting tumor microenvironments for cancer prevention and therapy.Book chapter in "Cancer Prevention - From Mechanisms to TranslationalBenefits", edited by Dr. Alexandros Georgakilas, InTech, ISBN978-953-51-0547-3, page 3-40. doi: 10.5772/28692.
Aishe Chen #,Lixue Dong #, Nancy R. Leffler, Adam S. Asch, Owen N. Witte, LiV. Yang * (2011). Activation of GPR4 by acidosis increases endothelial celladhesion through the cAMP/Epac pathway. PLOS ONE 6(11):e27586. doi: 10.1371/journal.pone.0027586.
Reid D. Castellone,Nancy R. Leffler, Lixue Dong, Li V. Yang * (2011). Inhibition of tumorcell migration and metastasis by the proton-sensing GPR4 receptor. CancerLetters 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 classificationof cultured cells through diffraction imaging. Biomedical Optics Express2(6):1717-1726.
Sun X, Yang LV, Tiegs BC, Arend LJ, McGraw DW, Penn RB, Petrovic S. Deletion of the pH Sensor GPR4 decreases renal acid excretion. J Am Soc Nephrol. 2010 Aug 26. [Epub ahead of print] PMID: 20798260
Jacobs KM, Yang LV, Ding J, Ekpenyong AE, Castellone R, Lu JQ, Hu XH. Diffraction imaging of spheres and melanoma cells with a microscope objective. J Biophotonics. 2009; 2(8-9):521-527. PMID: 19593764
Peter C, Waibel M, Radu CG, Yang LV, Witte ON, Schulze-Osthoff K, Wesselborg S, Lauber K. Migration to apoptotic "find-me" signals is mediated via the phagocyte receptor G2A. J Biol Chem. 2008; 283(9):5296-5305. PMID: 18089568
Yang LV, Radu CG, Roy M, Lee S, McLaughlin J, Teitell MA, Iruela-Arispe ML, Witte ON. Vascular abnormalities in mice deficient for the G protein-coupled receptor GPR4 that functions as a pH sensor. Mol Cell Biol. 2007; 27(4):1334-1347. PMID: 17145776
Yang LV, Wan J, Ge Y, Fu Z, Kim SY, Fujiwara Y, Taub JW, Matherly LH, Eliason J, Li L. The GATA site-dependent hemogen promoter is transcriptionally regulated by GATA1 in hematopoietic and leukemia cells. Leukemia. 2006; 20(3):417-425. PMID: 16437149
Radu CG, Cheng D, Nijagal A, Riedinger M, McLaughlin J, Yang LV, Johnson J, Witte ON. Normal immune development and glucocorticoid-induced thymocyte apoptosis in mice deficient for the T-cell death-associated gene 8 receptor. Mol Cell Biol. 2006; 26(2):668-677. PMID: 16382156
Wang L, Radu CG, Yang LV, Bentolila LA, Riedinger M, Witte ON. Lysophosphatidylcholine-induced surface redistribution regulates signaling of the murine G protein-coupled receptor G2A. Mol Biol Cell. 2005; 16(5):2234-2247. PMID: 15728718
Yang LV, Radu CG, Wang L, Riedinger M, Witte ON. Gi-independent macrophage chemotaxis to lysophosphatidylcholine via the immunoregulatory GPCR G2A. Blood. 2005; 105(3):1127-1134. PMID: 15383458
Radu CG, Yang LV, Riedinger M, Au M, Witte ON. T cell chemotaxis to lysophosphatidylcholine through the G2A receptor. Proc Natl Acad Sci USA. 2004; 101(1):245-250. PMID: 14681556
Yang LV, Heng HH, Wan J, Southwood CM, Gow A, Li L. Alternative promoters and polyadenylation regulate tissue-specific expression of Hemogen isoforms during hematopoiesis and spermatogenesis. Dev Dyn. 2003; 228(4):606-616. PMID: 14648837
Uhler J, Garbern J, Yang L, Kamholz J, Mellerick DM. Nk6, a novel Drosophila homeobox gene regulated by vnd. Mech Dev. 2002; 116(1-2):105-116. PMID: 12128210
Yang LV, Nicholson RH, Kaplan J, Galy A, Li L. 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. Mech Dev. 2001; 104(1-2):105-111. PMID: 11404085