Tulane University School of Medicine
Department of Pathology and Laboratory Medicine
1430 Tulane Ave., SL-79
New Orleans, LA 70112
1988 B.S. Molecular Biology and Physiology, University of Belgrade, Serbia
1992 M.S. Molecular Biology and Genetics Engineering, University of Belgrade, Serbia,
1999 Ph.D. University of Illinois at Chicago/ University of Belgrade Serbia
1999 – 2006: Postdoctoral fellow and Research Assistant professor, Mentor: Gail Hecht, MD, University of Illinois at Chicago
2006 - 2010: Research Assistant Professor, (Evanston-Northwestern-HealthSystem and Northwestern University, Evanston IL)
2010 - 2013: Assistant Professor (Northshore University HealthSystem, Evanston IL)
2013 – Present: Associate Professor, Tulane University School of Medicine
The main focus of my lab has been to study the role of the transcription factor FOXO3 in inflammation-mediated tumor growth, with a specific focus on the colonic epithelium and colon cancer. First, we have demonstrated that proinflammatory stimuli, such as bacterial products and cytokines, cause a loss of FOXO3 activity, leading to sustained inflammation in colonic epithelial cells, while deficiency of FOXO3 in mice increases susceptibility to colonic inflammation. Second, growth factors, known to support tumor progression, also cause loss of FOXO3, thus stimulating colonic tumor cell growth by loss of cell cycle arrest. These in vitro findings were confirmed in vivo, where a deficiency in FOXO3 lead to increased growth and promotion of colonic tumors, while inhibition of FOXO3 loss suppressed the growth of colonic tumor cells. Thus, as FOXO3 has anti-inflammatory and tumor suppressor functions in colonic cells, thus most likely the loss of FOXO3 is one of the contributors to inflammation-promoted tumor growth in the colon. Third, we found that FOXO3-deficient mice have increased accumulation of intracellular lipid droplets (LDs) and demonstrated the presence of cross-talk between FOXO3 and LDs as part of a regulatory network in colonic epithelial cells (non-transformed and transformed). Since inflammation and tumor growth have high metabolic needs, our goal is to determine that loss of FOXO3, which leads to increased LD accumulation, might provide metabolic energy to fuel inflammation and tumor growth and thus open an opportunity to establish new therapeutic approaches suppressing inflammation and tumor growth in the colon.
Epidemiological studies have found polymorphisms in the FOXO3 promoter in obese individuals. Moreover, increased intracellular accumulation of LDs characterizes obesity, thus potentially linking the regulatory network of FOXO3 and LDs with obesity. Since obesity is associated with inflammation (including intestinal inflammation), the cross-talk between FOXO3 and LDs may contribute to the increased risk of colonic tumors of obese subjects. Therefore, the second major focus of our lab is to determine the role of the LD-FOXO3 network in modulating susceptibility to colon tumor growth in experimental models of obesity-associated tumors.
1. Savkovic SD. Decreased FOXO3 within advanced human colon cancer: implications of tumor suppressor function. Br J Cancer, 2013; 109: 297
2. Qi W; Fitchev P; Cornwell M; Greenberg J; Cabe M; Weber CR; Roy H; Crawford S; Savkovic SD. FOXO3 Growth Inhibition of Colonic Cells is Dependent on Intraepithelial Lipid Droplet Density. J Biol Chem, 2013; 288(23): 16274.
3. Wali R; Kunte D’ De La Cruz M; Tiwari A; Brasky J; Weber CR; Gibson T; Patel A; Savkovic SD; Brockstein B; Roy HK. Topical Polyethylene Glycol as a Novel Chemopreventive Agent for Oral Cancer via Targeting of Epidermal Growth Factor Response. PloS ONE, 2012 7(6): e38047.
4. Qi W; Joshi S; Weber CR; Wali R; Roy H; Savkovic SD. Polyethylene glycol (PEG) diminishes pathological effects of Citrobacter rodentium infection by blocking bacterial attachment to the colonic epithelia. Gut Microbes, 2011, 2(5): 267.
5. Qi W; Weber CR, Wasland K; Savkovic SD. Genistein inhibits proliferation of colon cancer cells by attenuating a negative effect of epidermal growth factor on tumor suppressor FOXO3 activity. BMC Cancer 2011, 11(1): 219.
6. Qi W; Weber CR, Wasland K; Roy H, Wali R, Savkovic SD. Tumor suppressor FOXO3 mediates signals from the EGF receptor to regulate proliferation of colonic cells. Am J Physiology. 2011, 300(2): 72
7. Snoeks L, Weber CR, Wasland K; Turner JR; Savkovic SD. Tumor suppressor Foxo3a regulates intestinal inflammation in vitro and in vivo. Lab Investigation. 2009; 89:1053.
8. Snoeks L, Weber CR, Turner JR; Bhattacharyya M, Wasland K; Savkovic SD. Tumor suppressor Foxo3a is involved in the regulation of LPS-induced IL-8 in intestinal HT-29 cells. Infect Immun, 2008; 76:4677.
9. Savkovic SD; Villanueva J; Turner JR; Matkowskyj KA; Hecht G. Mouse model of enteropathogenic Escherichia coli infection. Infect Immun. 2005; 73:1161.
10. Tomson FL; Koutsouris A; Viswanathan VK; Turner JR; Savkovic SD; Hecht G. Differing roles of protein kinase C-zeta in disruption of tight junction barrier by enteropathogenic and enterohemorrhagic Escherichia coli. Gastro; 2004; 127:859
11. Savkovic SD; Koutsouris A; Hecht G. Enteropathogenic E.coli-activated PKC participate in intestinal epithelial inflammatory response. Am J Physiol; 2003; 285: C512.
12. Berkes, J; V.K. Viswanathan; Savkovic SD; Hecht G. Intestinal epithelial responses to enteric pathogens: Effects on the tight junction barrier, ion transport, and inflammation. Gut; 2003; 52: 439 (Review).
13. Savkovic SD; Ramaswamy A; Koutsouris A; Hecht G. Enteropathogenic E.coli-activated MAP kinases participate in intestinal epithelial inflammatory response but not perturbation of tight junction barrier. Am J Physiol; 2001; 281:G890.
14. Matdowskyj KA; Danilkovich A; Marrero JA; Savkovic SD; Hecht G; Benya RV. Galanin-1 receptor up-regulation mediates the excess colonic fluid production caused by infection with enteric pathogen. Nature Medicine; 2000; 6:1048
15. Savkovic SD; Koutsouris A; Wu G; Hecht, G. Infection of intestinal epithelial cells with bacterial pathogens decreases luciferase activity: Ramifications for reporter gene studies. Biotechniques; 2000; 29: 514-6 518-20 22.
16. Hecht G; Marrero JA; Danilkovich A; Matdowskyj KA; Savkovic SD; Koutsouris A; Benya RV. Infection of intestinal epithelial cells by pathogenic Escherichia coli upregulated galaanin-1 receptor expression: A novel mechanism of enhanced Cl- secretion. J. Clin. Invest; 1999; 3:253.
17. Savkovic SD; Koutsouris A; Hecht G. Activation of NF-kappaB in intestinal epithelial cells by enteropathogenic Escherichia coli. Am J Physiol; 1997; 273:C1160.
18. Hecht G; Savkovic SD. Effector role of epithelia in inflammation - Interaction with bacteria. Aliment Pharmacol Ther; 1997; 11 Suppl 3:64.
19. Yuhan R; Koutsouris A; Savkovic SD; Hecht G. Enteropathogenic Escherichia coli-induced myosin light chain phosphorylation alters intestinal epithelial permeability. Gastro; 1997; 113:1873.
20. Savkovic SD; Koutsouris A; Hecht G. Attachment of a noninvasive enteric pathogen, enteropathogenic Escherichia coli, to cultured human intestinal epithelial monolayers induces transmigration of neutrophils. Infect Immun; 1996; 64:4480.
21. Savkovic S; Pavlovic S; Mitrovic T; Joksimovic M; Marjanovic J; Glisin V; Popovic Z. Molecular evidence for increased hematopoietic proliferation in the spleen of the b/b laboratory rat. Experientia; 1996; 52:807.
22. Milosavljevic A; Savkovic S; Crkvenjakov R; Salbego D; Serrato H; Kreuzer H; Gemmell A; Batus S; Grujic D; Carnahan S; Tepavcevic J. Genome-scale DNA sequence recognition by hybridization to short oligomers. ISMB; 1996: 4:176.
23. Milosavljevic A; Savkovic, S; Crkvenjakov R; Salbego D; Serrato H; Kreuzer H; Gemmell A; Batus S; Grujic D; Carnahan S; Paunesku T; Tepavcevic J. DNA sequence recognition by hybridization to short oligomers: experimental verification of the method on the E. coli genome. Genomics; 1996; 37:77.
24. Marjanovic J; Savkovic,S; Nikcevic G; Glisin V; Ivanovic Z. Milenkovic N; Popovic Z. The disbalance of alpha and beta globins in anemic Belgrade rat red blood cells. Biochemical and Biophysical Research Communications; 1994; 201:115.
25. Popovic Z; Rajic N; Savkovic S; Glisin V. The "b" mutated gene in heterozygous Belgrade anemic rat. Exp. Hematology; 1993; 21:21.