Allan Tsung, MD



headshot
412-692-2001
Fax: 412-692-2002

UPMC Montefiore Liver Cancer Center and UPMC Montefiore Hospital

3459 Fifth Ave, 7 South

Pittsburgh, PA 15213

Roberta G. Simmons Endowed Professorship, Vice Chair of Research Division of Hepatobiliary and Pancreatic Surgery

Education

Cornell University, Ithaca, NY B.S. 1995

SUNY Health Science Center at Brooklyn, Brooklyn, NY M.D. 2000

Research Summary

The ongoing studies in my laboratory focus on innate immunity and the damage-associated molecular pattern (DAMP) danger response, specifically, the role of DAMPs and pattern recognition receptors in injury-induced inflammation and tumorigenesis of primary and metastatic liver cancer. My seminal findings implicate high mobility group box protein 1 (HMGB1) as an early mediator following acute, local organ injury, as in liver ischemia and reperfusion (I/R). I have developed my research program based on the hypothesis that ischemic parenchymal cells mobilize and release nuclear HMGB1 as a way to notify adjacent immune cells of impending tissue injury. This, in turn leads to activation of an inflammatory response that when excessive, contributes to further tissue damage. These inflammatory responses can also alter the local microenvironment leading to cancer progression via tumor cell survival, expansion, and metastases. My laboratory has recently demonstrated the novel finding that neutrophils can form neutrophil extracellular traps (NETs) in response to surgical stress to the liver (i.e. I/R) and that targeting NETs ameliorates the hepatic as well as systemic inflammation in mice. Our latest exciting findings demonstrate that increased NET formation following surgical stress of the liver also results in the acceleration of both the development and progression of metastatic disease. Because alterations in autophagy underlie mechanisms of a number of common hepatic diseases, I am also interested in understanding the roles that autophagy can play in normal hepatic physiology as well as in pathophysiological conditions, including hepatocellular carcinoma and I/R liver injury. The combination of these studies will provide a more comprehensive understanding of how inflammatory pathways promote organ injury after ischemic insults and should prove useful in the design of novel therapies to minimize tissue damage and improve liver function in a variety of disease states.

Lab Affiliation

Lab Role

P.I.

Publications

Inflammation and Cancer

Yan W, Chang Y, Liang X, Cardinal JS, Huang H, Thorne SH, Monga SP, Geller DA, Lotze MT, Tsung A. High mobility group box 1 activates caspase-1 and promotes hepatocellular carcinoma invasiveness and metastases. Hepatology. 2012; 55(6):1863-75.

Chang Y, Yan W, He X, Zhang L, Li C, Huang H, Nace G, Geller DA, Lin J, Tsung A. miR-375 Inhibits Autophagy and Reduces Viability of Hepatocellular Carcinoma Cells Under Hypoxic Conditions. Gastroenterology. 2012; 143(1):177-187.

Liu Y, Yan W, Tohme S, Chen M, Fu Y, Tian D, Lotze M, Tang D, Tsung A. Hypoxia induced HMGB1 and mitochondrial DNA interactions mediate tumor growth in hepatocellular carcinoma through Toll Like Receptor 9. J Hepatol. 2015; 63(1):114-21. 

Tohme S, Yazdani HO, Al-Khafaji AB, Chidi  AP, Loughran P,  Mowen K, Wang Y,  Simmons RL, Huang H, Tsung A. Neutrophil Extracellular Traps Promote the Development and Progression of Liver Metastases after Surgical Stress. Cancer Res. 2016; 76(6):1367-80. 

Innate Immune Response to Liver Injury

Tsung A, Sahai R, Tanak H, Nakao A, Fink MP, Lotze MT, Yang H, Li J, Tracey KJ, Geller DA, Billiar TR. The nuclear factor HMGB1 mediates hepatic injury after murine liver ischemia-reperfusion. J Exp Med. 2005; 205:1-10.

Tsung A, Klune JR, Zhang X, Jeyabalan G, Cao Z, Peng X, Stolz DB, Geller DA, Rosengart MR, Billiar TR. Ischemia-induced HMGB1 Release by Hepatocytes Involves Toll-like Receptor 4 Dependent Reactive Oxygen Species Production and Calcium Mediated Signaling. J Exp Med. 2007; 204(12):2913-23.

Huang H, Nace GW, McDonald KA, Tai S, Klune JR, Rosborough BR, Ding Q, Loughran P, Zhu X, Beer-Stolz D, Chang EB, Billiar T, Tsung A. Hepatocyte specific HMGB1 deletion worsens the injury in liver ischemia/reperfusion: A role for intracellular HMGB1 in cellular protection. Hepatology. 2014; 59(5):1984-97.

Huang H, Tohme S, Al-Khafaji AB, Loughran P, Chen L, Wang S, Kim J, Billiar T, Wang Y, Tsung A. DAMPs-activated neutrophil extracellular trap exacerbates sterile inflammatory liver injury. Hepatology. 2015;62(2):600-14.

Autophagy and Liver Disease

Chang Y, Yan W, He X, Zhang L, Li C, Huang H, Nace G, Geller DA, Lin J, Tsung A. miR-375 Inhibits Autophagy and Reduces Viability of Hepatocellular Carcinoma Cells Under Hypoxic Conditions. Gastroenterology. 2012; 143(1):177-187.

Evankovich J, Zhang R, Cardinal JS, Zhang L, Chen J, Huang H, Beer-Stolz D, Billiar TR, Rosengart MR, Tsung A. Calcium/Calmodulin-Dependent Protein Kinase IV limits organ damage in hepatic ischemia/reperfusion injury through induction of autophagy. Am J Physiol Gastrointest Liver Physiol. 2012; 303(2):G189-98. 

Czaja MJ, Ding WX, Donohue TM, Friedman SL, Kim JS, Komatsu M, Lemasters JJ, Lemoine A, Lin JD, Ou JH, Perlmutter DH, Randall G, Ray RB, Tsung A, Yin XM. Functions of autophagy in normal and diseased liver. Autophagy. 2013; 9(8):1131-58.