Li Yang, PhD, Research

Research

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

Li Yang, PhD
Professor
Division of Hematology /Oncology
600 Moye Blvd., Brody 3E127
Greenville, NC 27834
252-744-3419
252-744-3418 (fax)
yangl@ecu.edu

Selected Publications

2023

Mona A. Marie, Edward J. Sanderlin, Alexander P. Hoffman, Kylie D. Cashwell, Swati Satturwar, Heng Hong, Ying Sun, Li V. Yang (2023). GPR4 knockout attenuates intestinal inflammation and forestalls the development of colitis-associated colorectal cancer in murine models. Cancers, 15(20):4974. doi: 10.3390/cancers15204974.

Abdul Rafeh Naqash, Justin D. McCallen, Emma Mi, Sanna Iivanainen, Mona A. Marie, Daria Gramenitskaya, James Clark, Jussi Pekka Koivunen, Shravanti Macherla, Sweta Jonnalagadda, Shanker Polsani, Rahim Ali Jiwani, Maida Hafiz, Mahvish Muzaffar, Leonardo Brunetti, Chipman R.G. Stroud, Paul R. Walker, Kun Wang, Youngmin Chung, Eytan Ruppin, Se-Hoon Lee, Li V. Yang, David J. Pinato, Joo Sang Lee, Alessio Cortellini (2023). Increased interleukin-6/C-reactive protein levels are associated with the upregulation of the adenosine pathway and serve as potential markers of therapeutic resistance to immune checkpoint inhibitor-based therapies in non-small cell lung cancer. Journal for ImmunoTherapy of Cancer, 11:e007310. doi:10.1136/jitc-2023-007310.

Calvin R. Justus, Mona A. Marie, Edward J. Sanderlin, Li V. Yang (2023). Transwell in vitro cell migration and invasion assays. Oliver Friedrich and Daniel F. Gilbert (eds.), Cell Viability Assays: Methods and Protocols, Methods in Molecular Biology, 2644:349-359. https://doi.org/10.1007/978-1-0716-3052-5_22.

2022

Mona A. Marie, Edward J. Sanderlin, Swati Satturwar, Heng Hong, Kvin Lertpiriyapong, Deepak Donthi, Li V. Yang (2022). GPR65 (TDAG8) inhibits intestinal inflammation and colitis-associated colorectal cancer development in experimental mouse models. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease. 1868: 166288. doi: 10.1016/j.bbadis.2021.166288.

Mona A. Marie, Justin D. McCallen, Zahra S. Hamedi, Abdul Rafeh Naqash, Alexander Hoffman, Druid Atwell, Suneetha Amara, Mahvish Muzaffar, Paul R. Walker, Li V. Yang (2022). Peripheral blood T cells and inflammatory biomarkers in lung cancer patients with immune checkpoint inhibitor-induced thyroid dysfunction: case studies and literature review. Frontiers in Oncology 12:1023545. doi: 10.3389/fonc.2022.1023545.

Suneetha Amara, Li V. Yang, Venkataswarup Tiriveedhi, Mahvish Muzaffar (2022). Complex Role of Microbiome in Pancreatic Tumorigenesis: Potential Therapeutic Implications. Cells 11(12): 1900. https://doi.org/10.3390/cells11121900.

James A. McCubrey, Li V. Yang, Stephen L. Abrams, Linda S. Steelman, Matilde Y. Follo, Lucio Cocco, Stefano Ratti, Alberto M. Martelli, Giuseppa Augello, Melchiorre Cervello (2022). Effects of TP53 Mutations and miRs on Immune Responses in the Tumor Microenvironment Important in Pancreatic Cancer Progression. Cells 11(14): 2155. https://doi.org/10.3390/cells11142155.

2021

Justin D. McCallen, Abdul Rafeh Naqash, Mona A. Marie, Druid C. Atwell, Mahvish Muzaffar, Nitika Sharma, Suneetha Amara, Darla Liles, Paul R. Walker, Li V. Yang (2021). Peripheral Blood Interleukin 6, Interleukin 10, and T Lymphocyte Levels are Associated with Checkpoint Inhibitor Induced Pneumonitis: A Case Report. Acta Oncologica 60: 813-817. doi: 10.1080/0284186X.2021.1917001.

Li V. Yang, Karen A. Oppelt, Mary Jane Thomassen, Mona A. Marie, Shayan Nik Akhtar, Justin D. McCallen (2021). Can GPR4 be a potential therapeutic target for COVID-19?  Frontiers in Medicine 7:626796. doi: 10.3389/fmed.2020.626796.

2020

Elizabeth A. Krewson, Edward J. Sanderlin, Mona A. Marie, Shayan Nik Akhtar, Juraj Velcicky, Pius Loetscher, Li V. Yang (2020). The proton-sensing GPR4 receptor regulates paracellular gap formation and permeability of vascular endothelial cells. iScience 23: 100848. doi: https://doi.org/10.1016/j.isci.2020.100848.

2019

Edward J. Sanderlin, Mona Marie, Juraj Velcicky, Pius Loetscher, Li V. Yang (2019). Pharmacological inhibition of GPR4 remediates intestinal inflammation in a mouse colitis model. European Journal of Pharmacology 852: 218-230. doi: 10.1016/j.ejphar.2019.03.038.

Abdul Rafeh Naqash, Ebenezer Appah, Li V. Yang, Mahvish Muzaffar, Mona A. Marie, Justin D. Mccallen, Shravanti Macherla, Darla Liles, Paul R. Walker (2019). Isolated neutropenia as a rare but serious adverse event secondary to immune checkpoint inhibition. Journal for ImmunoTherapy of Cancer 7: 106. doi: 10.1186/s40425-019-0648-3.

2018

Abdul Rafeh Naqash, Li V. Yang, Edward J. Sanderlin, Druid C. Atwell, Paul R. Walker (2018). Interleukin-6 as one of the potential mediators of immune-related adverse events in non-small cell lung cancer patients treated with immune checkpoint blockade: evidence from a case report. Acta Oncologica 57: 705-708. doi: 10.1080/0284186X.2017.1406668.

Abdul Rafeh Naqash, Chipman Robert Geoffrey Stroud, Mohammad Umer Butt, Grace K. Dy, Aparna Hegde, Mahvish Muzaffar, Li V. Yang, Maida Hafiz, Cynthia R. Cherry, Paul R. Walker (2018). Co-relation of overall survival with peripheral blood-based inflammatory biomarkers in advanced stage non-small cell lung cancer treated with anti-programmed cell death-1 therapy: results from a single institutional database. Acta Oncologica 57(6):867-872. doi: 10.1080/0284186X.2017.1415460.

Stephen L. Abrams, Kvin Lertpiriyapong, Li V. Yang, Alberto M. Martelli, Lucio Cocco, Stefano Ratti, Marco Falasca, Ramiro M. Murata, Pedro L. Rosalen, Paolo Lombardi, Massimo Libra, Saverio Candido, Giuseppe Montalto, Melchiorre Cervello, Linda S. Steelman, James A. McCubrey (2018). Introduction of WT-TP53 into pancreatic cancer cells alters sensitivity to chemotherapeutic drugs, targeted therapeutics and nutraceuticals. Advances in Biological Regulation 69: 16-34. doi: 10.1016/j.jbior.2018.06.002.

2017

Li V. Yang (2017). Tumor microenvironment and metabolism. International Journal of Molecular Sciences 18(12): 2729. doi: 10.3390/ijms18122729.

Calvin R. Justus, Edward J. Sanderlin, Lixue Dong, Tianai Sun, Jen-Tsan Chi, Kvin Lertpiriyapong, Li V. Yang (2017). Contextual tumor suppressor function of T cell death-associated gene 8 (TDAG8) in hematological malignancies. Journal of Translational Medicine 15: 204. doi: 10.1186/s12967-017-1305-6.

Lixue Dong, Elizabeth A. Krewson, Li V. Yang (2017). Acidosis activates endoplasmic reticulum stress pathways through GPR4 in human vascular endothelial cells. International Journal of Molecular Sciences 18(2): E278. doi: 10.3390/ijms18020278.

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.

Yuhua Wen, Zhan Chen, Jianfen Lu, Elizabeth Ables, Jean-Luc Scemama, Li V. Yang, Jun Q. Lu, Xin-Hua Hu (2017). Quantitative analysis and comparison of 3D morphology between viable and apoptotic MCF-7 breast cancer cells and characterization of nuclear fragmentation. PLoS ONE 12(9): e0184726. doi: 10.1371/journal.pone.0184726.

James A. McCubrey, Kvin Lertpiriyapong, Linda S. Steelman, Steve L. Abrams, Li V.Yang, Ramiro M. Murata, Pedro L. Rosalen, Aurora Scalisi, Luca M. Neri, Lucio Cocco,Stefano Ratti, Alberto M. Martelli, Piotr Laidler, Joanna Dulińska-Litewka, Dariusz Rakus, Agnieszka Gizak, Paolo Lombardi, Ferdinando Nicoletti, Saverio Candido, Massimo Libra, Giuseppe Montalto, Melchiorre Cervello (2017). Effects of resveratrol, curcumin, berberine and other nutraceuticals on aging, cancer development, cancer stem cells and microRNAs. Aging 9(6): 1477-1536. doi: 10.18632/aging.101250.

Daniel A. Ladin, Eman Soliman, Rene Escobedo, Timothy L. Fitzgerald, Li V. Yang, Colin Burns, Rukiyah Van Dross (2017). Synthesis and evaluation of the novel prostamide, 15-deoxy-Δ^12,14-prostamide J₂, as a selective anti-tumor therapeutic. Molecular Cancer Therapeutics 16(5): 838-849. doi: 10.1158/1535-7163.MCT-16-0484.

James A. McCubrey, Timothy L. Fitzgerald, Li V. Yang, Kvin Lertpiriyapong, Linda S. Steelman, Stephen L. Abrams, Giuseppe Montalto, Melchiorre Cervello, Luca M. Neri, Lucio Cocco, Alberto M. Martelli, Piotr Laidler, Joanna Dulińska-Litewka, Dariusz Rakus, Agnieszka Gizak, Ferdinando Nicoletti, Luca Falzone, Saverio Candido, Massimo Libra (2017). Roles of GSK-3 and microRNAs on Epithelial Mesenchymal Transition and Cancer Stem Cells. Oncotarget 8: 14221-14250. doi: 10.18632/oncotarget.13991.

James A. McCubrey, Kvin Lertpiriyapong, Timothy L. Fitzgerald, Alberto M. Martelli, Lucio Cocco, Dariusz Rakus, Agnieszka Gizak, Massimo Libra, Melchiorre Cervello, Guiseppe Montalto, Li V. Yang, Stephen L. Abrams, Linda S. Steelman (2017). Roles of TP53 in Determining Therapeutic Sensitivity, Growth, Cellular Senescence, Invasion and Metastasis. Advances in Biological Regulation 63: 32-48. doi: 10.1016/j.jbior.2016.10.001.

2016

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.

2015

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.

2014

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.

2013

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.

2012

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.

2011

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.

2010

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.

Before 2010

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 Development116:105-116.

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.