Member Biography

Mark Geraci, M.D.

545 Barnhill Drive
Emerson Hall 317
Indianapolis, IN 46202

Phone: (317) 274-8438
Fax: (317) 274-1437

Research Program Membership

Chair and John B. Hickam Professor of Medicine
Department of Medicine
IU School of Medicine

Our work in lung carcinogenesis has focused on translational studies examining the role of eicosanoids (in particular prostacyclin, PGI2) in the development of lung tumors. We were able to demonstrate that selective overexpression of PGI2 within the lungs of transgenic mice that we created were protected from the development of tumors (ultimately in 3 distinct tumorigenesis models). Mechanistically, we discovered that prostacyclin prevented cigarette smoke endothelial apoptosis by an SP1-mediated effect. Furthermore, we discovered that the effects of PGI2 were not mediated through the canonical membrane receptor; rather through a novel interaction with PPARγ. These results were translated into the first successful human trial demonstrating that Iloprost (a PGI2 analog) reversed endobronchial dysplasia in patients in a phase 2b trial. a. Keith, R. L., Miller, Y. E., Hoshikawa, Y., Moore, M. D., Gesell, T. L., Gao, B., Malkinson, A. M., Golpon, H. A., Nemenoff, R. A., and Geraci, M. W. Manipulation of Pulmonary Prostacyclin Synthase Expression Prevents Murine Lung Cancer. Cancer Res., 62: 734-740, 2002. PMID:11830527 b. Nana-Sinkam,S.P., Lee,J.D., Sotto-Santiago,S., Stearman,R.S., Keith,R.L., Choudhury,Q., Cool,C., Parr,J., Moore,M.D., Bull,T.M., Voelkel,N.F. and Geraci,M.W. Prostacyclin prevents pulmonary endothelial cell apoptosis induced by cigarette smoke, Am.J.Respir.Crit Care Med., 175: 676-685, 2007. PMID:17255567; PMCID: PMC1899287 c. Nemenoff,R., Meyer,A.M., Hudish,T.M., Mozer,A.B., Snee,A., Narumiya,S., Stearman,R.S., Winn,R.A., Weiser-Evans,M., Geraci,M.W. et al. Prostacyclin prevents murine lung cancer independent of the membrane receptor by activation of peroxisomal proliferator--activated receptor gamma. Cancer Prev. Res. (Phila Pa) 1:349-356, 2008. PMID:19138979; PMCID: PMC2680197 d. Keith RL, Blatchford PJ, Kittelson J, Minna JD, Kelly K, Massion PP, Franklin WA, Mao J, Wilson DO, Merrick DT, Hirsch FR, Kennedy TC, Bunn PA, Jr., Geraci MW, Miller YE. Oral Iloprost Improves Endobronchial Dysplasia in Former Smokers. Cancer Prev Res (Phila) 4: 793-802, 2011. PMID: 21636546; PMCID: PMC3251330 2. As founding director of the University of Colorado Genomics Facility in 199, our group has extensively utilized genomic technologies to explore pathogenesis as well as biomarker development in lung cancer investigation. We were able to develop a comprehensive atlas of orthologous gene expression changes between our murine urethane model and human adenocarcinoma. Also, we utilized predictive modeling and classification strategies to define gene expression signatures which predict EGFR TKI sensitivity (This was eventually patented and licensed). Our work in the tumor microenvironment defined, for the first time, the field carcinogenesis factors representing the critical importance of macrophages within the microenvironment. Most recently, we utilized as sensitive and novel computational tool (delta-theta) comparing chromosomal aberrations within premalignant lesions by comparing blood copy number to lesion copy number within the premalignant airway as a more sensitive measure for premalignant biology with the identification of several novel tumor suppressor genes. a. Stearman,R.S., Dwyer-Nield,L., Zerbe,L., Blaine,S.A., Chan,Z., Bunn,P.A., Jr., Johnson,G.L., Hirsch,F.R., Merrick,D.T., Franklin,W.A., Baron,A.E., Keith,R.L., Nemenoff,R.A., Malkinson,A.M. and Geraci,M.W. Analysis of orthologous gene expression between human pulmonary adenocarcinoma and a carcinogen-induced murine model, Am.J.Pathol., 167: 1763-1775, 2005. PMID:16314486; PMCID: PMC1613183 b. Coldren,C.D., Helfrich,B.A., Witta,S.E., Sugita,M., Lapadat,R., Zeng,C., Baron,A., Franklin,W.A., Hirsch,F.R., Geraci,M.W. and Bunn,P.A., Jr. Baseline gene expression predicts sensitivity to gefitinib in non-small cell lung cancer cell lines, Mol. Cancer Res., Aug;4: 21-528, 2006. PMID:16877703 c. Stearman,R.S., Dwyer-Nield,L., Grady,M.C., Malkinson,A.M. and Geraci,M.W. A macrophage gene expression signature defines a field effect in the lung tumor microenvironment, Cancer Res., Jan 1;68(1):34-43, 2008. PMID:18172294 d. Nakachi, I., Rice, J. L., Coldren, C. D., Edwards, M. G., Stearman, R. S., Glidewell, S. C., Varella-Garcia, M., Franklin, W. A., Keith, R. L., Lewis, M. T., Gao, B., Merrick, D. T., Miller, Y. E., and Geraci, M. W. (2014) Application of SNP microarrays to the genome-wide analysis of chromosomal instability in premalignant airway lesions. Cancer Prevention Research 7, 255-265 PubMed Central ID: 3. We were the first group to apply genomic technologies to the study of human tissue samples in patients with pulmonary hypertension, uncovering many new pathways that continue to be explored by us and other groups for models of pathogenesis. Furthermore, we were the first group to analyze gene expression signatures within the blood of patients with pulmonary arterial hypertension (PAH) as a surrogate to tissue gene expression. These studies enabled our focus on inflammatory pathways as potential mediators and contributors to pulmonary hypertension. We provided an invaluable resource to the pulmonary community by publishing a large case series of ¿control¿ human lung samples and explored regional variations in gene expression (minimal) versus age, versus smoking status and described gene signatures for each. Most recently, we demonstrated, for the first time, that somatic chromosomal alterations occur exclusively within the endothelial cells of patients with PAH. These data strongly support the cancer paradigm of the etiology of PAH. a. Geraci, M. W., Moore, M., Gesell, T., Yeager, M. E., Alger, L., Golpon, H., Gao, B., Loyd, J. E., Tuder, R. M., and Voelkel, N. F. Gene expression patterns in the lungs of patients with primary pulmonary hypertension: a gene microarray analysis. Circ Res 2001 Mar 30;88(6):555-562. PMID: 11282888; PMCID: b. Bull, T. M., Coldren, C. D., Moore, M., Sotto-Santiago, S. M., Pham, D. V., Nana-Sinkam, S. P., Voelkel, N. F., and Geraci, M. W. Gene microarray analysis of peripheral blood cells in pulmonary arterial hypertension. Am J Respir Crit Care Med 2004 Oct 15;170(8):911-919. Epub 2004 Jun 23. PMID: 15215156; PMCID: c. Gruber, M. P., Coldren, C. D., Woolum, M. D., Cosgrove, G. P., Zeng, C., Baron, A. E., Moore, M. D., Cool, C. D., Worthen, G. S., Brown, K. K., and Geraci, M. W. Human lung project: evaluating variance of gene expression in the human lung. Am J Respir Cell Mol Biol 2006 Jul;35(1):65-71. Epub 2006 Feb 23. PMID: 16498083; PMCID: PMC2658699 d. Aldred MA, Comhair SA, Varella-Garcia M, Asosingh K, Xu W, Noon GP, Thistlethwaite PA, Tuder RM, Erzurum SC, Geraci MW, Coldren CD. Somatic Chromosome Abnormalities in the Lungs of Patients with Pulmonary Arterial Hypertension. Am J Respir Crit Care Med 182(9):1153-1160, 2010. PMID:20581168; PMCID: PMC3001257 4. We have spent extensive efforts examining the basic pathophysiologic mechanisms of pulmonary hypertension and the effects of PGI2 on the pathogenesis of the disease. We created lung-specific transgenic animals and demonstrated that overexpression of the PGI Synthase gene (which I cloned) protects against the development of PAH in an animal model. Moreover, we were the first group to demonstrate that the virus, HHV8 is associated with PAH in a significant fraction (nearly 2/3) of PAH patients. In the same line of research, we demonstrated that IL-6 is a critical mediator of Schistosoma-Pulmonary hypertension, the most common cause of PAH world-wide. In collaboration with the Vanderbilt group, we were able to demonstrate that functional genetic polymorphisms within the PGI synthase gene are associated with the development of the disease and that PGI Synthase may act as a modifier gene in patients who carry BMPR2 mutations. a. Geraci, M. W., Gao, B., Shepherd, D. C., Moore, M. D., Westcott, J. Y., Fagan, K. A., Alger, L. A., Tuder, R. M., and Voelkel, N. F. Pulmonary prostacyclin synthase overexpression in transgenic mice protects against development of hypoxic pulmonary hypertension. J Clin Invest 1999 Jun;103(11):1509-1515. PMID: 10359560; PMCID: PMC408370 b. Cool, C. D., Rai, P. R., Yeager, M. E., Hernandez-Saavedra, D., Serls, A. E., Bull, T. M., Geraci, M. W., Brown, K. K., Routes, J. M., Tuder, R. M., and Voelkel, N. F. Expression of human herpesvirus 8 in primary pulmonary hypertension. N Engl J Med 2003 Sep 18;349(12):1113-1122. PMID: 13679525; PMCID: c. Graham, B. B., Chabon, J., Kumar, R., Kolosionek, E., Gebreab, L., Debella, E., Edwards, M., Diener, K., Shade, T., Bifeng, G., Bandeira, A., Butrous, G., Jones, K., Geraci, M., and Tuder, R. M. Protective Role of IL6 in Vascular Remodeling in Schistosoma-Pulmonary Hypertension. Am J Respir Cell Mol Biol 2013 Jul 1. [Epub ahead of print] PMID: 23815102; PMCID: d. Stearman, R.S., Cornelius, A.R., Liu, X., Conklin, D.S., Del Rosario, M.J., Lowe, A.M., Elos, M.T., Wong, R.E., Hara, N., Cogan, J.D., Phillips, J.A., Taylor, M.R., Graham, B.B., Tuder, R.M., Loyd, J.E., and Geraci, M.W. Functional prostacyclin synthase promoter polymorphisms: Impact in pulmonary arterial hypertension. American Journal of Respiratory and Critical Care Medicine, 2014, 189, 1110-1120. Complete List of Published Work in MyBibliography:

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Fellowship - University of Colorado, Denver, CO 1994

Residency - Massachusetts General Hospital, Boston, MA 1990

M.D. - The Johns Hopkins University School of Medicine, Baltimore, MD 1983