Center for Matrix Biology - Vanderbilt University and Medical Center

Ambra Pozzi, Ph.D.
Associate Professor in the Department of Medicine

	Office Address:	S-3223 MCN
	Mailing Address:	S-3223 MCN Nashville, TN 2372
	Lab address:
	Phone:	615-322-4637
		email

Secondary appointment in the Cancer Biology department.

Research Summary

We use gene-targeting technology to study integrins, transmembrane receptors for extracellular matrix components. We study integrin a1b1 one of the major collagen binding receptor. Using integrin a1-null mice we demonstrated that this integrin is the only collagen binding receptor able to control i) cell survival and proliferation, ii) collagen and metalloproteinase synthesis and iii) angiogenesis, the process of new blood vessel formation. As angiogenesis is essential for tumor growth and development, blocking this process might be a valid tool for the control of tumor growth. We observed that in integrin a1-null mice tumor angiogenesis is markedly reduced compared to that of wild type animals. This reduction is due to over-expression of matrix metalloproteinases (mainly gelatinase B or MMP9) in the a1-null and consequent generation of angiostatin (an inhibitor of endothelial cell growth) from circulating plasminogen. Thus these observations seem to support the paradigm that excess synthesis of metalloproteinases may prevent primary tumor growth via angiostatin generation. We are now investigating how the metalloproteinase/angiostatin axis controls tumor vascularization and how stimulation of this pathway can be used in vivo as a valid tool to reduce and ideally inhibit tumor growth and vascularization.

Research Keywords

Diabetes, Kidney, Mouse, Receptor, Signal transduction, Vascular Biology,

Printer Friendly

Associated initiative(s):

Angiogenesis

Fibrosis

Tissue Regeneration

Tumor Microenvironment

Career opportunities:
None currently available

Selected Publications

» Woodall, BP, Nystr??m, A, Iozzo, RA, Eble, JA, Niland, S, Krieg, T, Eckes, B, Pozzi, A, Iozzo, RV Integrin alpha2beta1 is the required receptor for endorepellin angiostatic activity J Biol Chem 2008. 283:2335-43

» Erdogan, M, Pozzi, A, Bhowmick, N, Moses, HL, Zent, R Transforming growth factor-beta (TGF-beta) and TGF-beta-associated kinase 1 are required for R-Ras-mediated transformation of mammary epithelial cells Cancer Res 2008. 68:6224-31

» Macias-Perez, I, Borza, C, Chen, X, Yan, X, Ibanez, R, Mernaugh, G, Matrisian, LM, Zent, R, Pozzi, A Loss of integrin alpha1beta1 ameliorates Kras-induced lung cancer Cancer Res 2008. 68:6127-35

» Pozzi, A, Jarad, G, Moeckel, GW, Coffa, S, Zhang, X, Gewin, L, Eremina, V, Hudson, BG, Borza, DB, Harris, RC, Holzman, LB, Phillips, CL, Fassler, R, Quaggin, SE, Miner, JH, Zent, R Beta1 integrin expression by podocytes is required to maintain glomerular structural integrity Dev Biol 2008. 316:288-301

» Borza, CM, Borza, DB, Pedchenko, V, Saleem, MA, Mathieson, PW, Sado, Y, Hudson, HM, Pozzi, A, Saus, J, Abrahamson, DR, Zent, R, Hudson, BG Human podocytes adhere to the KRGDS motif of the alpha3alpha4alpha5 collagen IV network J Am Soc Nephrol 2008. 19:677-84

» Pozzi, A, Zent, R Integrins, extracellular matrix, and terminal differentiation of renal epithelial cells J Am Soc Nephrol 2008. 19:1043-4

» Cosgrove, D, Meehan, DT, Delimont, D, Pozzi, A, Chen, X, Rodgers, KD, Tempero, RM, Zallocchi, M, Rao, VH Integrin alpha1beta1 regulates matrix metalloproteinases via P38 mitogen-activated protein kinase in mesangial cells: implications for Alport syndrome Am J Pathol 2008. 172:761-73

» Abair, TD, Bulus, N, Borza, C, Sundaramoorthy, M, Zent, R, Pozzi, A Functional Analysis of the cytoplasmic domain of the integrin {alpha}1 subunit in endothelial cells Blood 2008. :

» Zhang, Z, Ramirez, NE, Yankeelov, TE, Li, Z, Ford, LE, Qi, Y, Pozzi, A, Zutter, MM alpha2beta1 integrin expression in the tumor microenvironment enhances tumor angiogenesis in a tumor cell-specific manner Blood 2008. 111:1980-8

» Macias-Perez, IM, Zent, R, Carmosino, M, Breyer, MD, Breyer, RM, Pozzi, A Mouse EP3 alpha, beta, and gamma receptor variants reduce tumor cell proliferation and tumorigenesis in vivo J Biol Chem 2008. 283:12538-45

» Chen, X, Abair, TD, Ibanez, MR, Su, Y, Frey, MR, Dise, RS, Polk, DB, Singh, AB, Harris, RC, Zent, R, Pozzi, A Integrin alpha1beta1 controls reactive oxygen species synthesis by negatively regulating epidermal growth factor receptor-mediated Rac activation Mol Cell Biol 2007. 27:3313-26

» Kanjanabuch, T, Ma, LJ, Chen, J, Pozzi, A, Guan, Y, Mundel, P, Fogo, AB PPAR-gamma agonist protects podocytes from injury Kidney Int 2007. :

» Pozzi, A, Ibanez, MR, Gatica, AE, Yang, S, Wei, S, Mei, S, Falck, JR, Capdevila, JH Peroxisomal proliferator activated receptor(alpha)-dependent inhibition of endothelial cell proliferation and tumorigenesis J Biol Chem 2007. :

» Zhang, H, Lawson, WE, Polosukhin, VV, Pozzi, A, Blackwell, TS, Litingtung, Y, Chiang, C Inhibitor of differentiation 1 promotes endothelial survival in a bleomycin model of lung injury in mice Am J Pathol 2007. 171:1113-26

» Erdogan, M, Pozzi, A, Bhowmick, N, Moses, HL, Zent, R Signaling pathways regulating TC21-induced tumorigenesis J Biol Chem 2007. 282:27713-20

» Rao, R, Redha, R, Macias-Perez, I, Su, Y, Hwang, MT, Hao, C, Zent, R, Breyer, MD, Pozzi, A Prostaglandin E2-EP4 receptor promotes endothelial cell migration via ERK activation and angiogenesis in vivo J Biol Chem 2007. :

» Zent, R, Pozzi, A Angiogenesis in diabetic nephropathy Semin Nephrol 2007. 27:161-71

» Pozzi, A, Coffa, S, Bulus, N, Zhu, W, Chen, D, Chen, X, Mernaugh, G, Su, Y, Cai, S, Singh, A, Brissova, M, Zent, R H-Ras, R-Ras, and TC21 Differentially Regulate Ureteric Bud Cell Branching Morphogenesis Mol Biol Cell 2006. :

» Nakagawa, K, Holla, VR, Wei, Y, Wang, WH, Gatica, A, Wei, S, Mei, S, Miller, CM, Cha, DR, Price, E, Zent, R, Pozzi, A, Breyer, MD, Guan, Y, Falck, JR, Waterman, MR, Capdevila, JH Salt-sensitive hypertension is associated with dysfunctional Cyp4a10 gene and kidney epithelial sodium channel J Clin Invest 2006. 116:1696-702

» Borza, CM, Pozzi, A, Borza, DB, Pedchenko, V, Hellmark, T, Hudson, BG, Zent, R Integrin alpha3beta1, a novel receptor for alpha3(IV) noncollagenous domain and a trans-dominant Inhibitor for integrin alphavbeta3 J Biol Chem 2006. 281:20932-9

» Kamiyama, M, Pozzi, A, Yang, L, DeBusk, LM, Breyer, RM, Lin, PC EP2, a receptor for PGE2, regulates tumor angiogenesis through direct effects on endothelial cell motility and survival Oncogene 2006. 25:7019-28

» Zent, R, Yan, X, Su, Y, Hudson, BG, Borza, DB, Moeckel, GW, Qi, Z, Sado, Y, Breyer, MD, Voziyan, P, Pozzi, A Glomerular injury is exacerbated in diabetic integrin alpha1-null mice Kidney Int 2006. 70:460-70

» Liang, XB, Ma, LJ, Naito, T, Wang, Y, Madaio, M, Zent, R, Pozzi, A, Fogo, AB Angiotensin type 1 receptor blocker restores podocyte potential to promote glomerular endothelial cell growth J Am Soc Nephrol 2006. 17:1886-95

» Acuff, HB, Sinnamon, M, Fingleton, B, Boone, B, Levy, SE, Chen, X, Pozzi, A, Carbone, DP, Schwartz, DR, Moin, K, Sloane, BF, Matrisian, LM Analysis of host- and tumor-derived proteinases using a custom dual species microarray reveals a protective role for stromal matrix metalloproteinase-12 in non-small cell lung cancer Cancer Res 2006. 66:7968-75

» Mu??oz, NM, Upton, M, Rojas, A, Washington, MK, Lin, L, Chytil, A, Sozmen, EG, Madison, BB, Pozzi, A, Moon, RT, Moses, HL, Grady, WM Transforming growth factor beta receptor type II inactivation induces the malignant transformation of intestinal neoplasms initiated by Apc mutation Cancer Res 2006. 66:9837-44

» Zent, R, Pozzi, A Antiangiogenic Therapy in Diabetic Nephropathy J Am Soc Nephrol 2006. :

» Moeckel, GW, Zhang, L, Chen, X, Rossini, M, Zent, R, Pozzi, A Role of integrin alpha1beta1 in the regulation of renal medullary osmolyte concentration Am J Physiol Renal Physiol 2006. 290:F223-31

» Chen, X, Su, Y, Fingleton, B, Acuff, H, Matrisian, LM, Zent, R, Pozzi, A Orthotopic models of lung cancer to follow primary and metastatic NSCLC growth in integrin α1-null mice Clin. Exp. Metastasis 2005, In press. :

» Frank, DB, Abtahi, A, Yamaguchi, DJ, Manning, S, Shyr, Y, Pozzi, A, Baldwin, HS, Johnson, JE, de Caestecker, MP Bone morphogenetic protein 4 promotes pulmonary vascular remodeling in hypoxic pulmonary hypertension Circ Res 2005. 97:496-504

» Mernaugh, RL, Yan, H, Chen, D, Edl, J, Hanley, G, Pozzi, A, Zent, R Production and characterization of mouse ureteric bud cell-specific rat hybridoma antibodies utilizing subtractive immunization and high-throughput screening J Immunol Methods 2005. 306:115-27

» Cai, S, Bulus, N, Fonseca-Siesser, PM, Chen, D, Hanks, SK, Pozzi, A, Zent, R CD98 modulates integrin beta1 function in polarized epithelial cells J Cell Sci 2005. 118:889-99

» Pozzi, A, Macias-Perez, I, Abair, T, Wey, S, Su, Y, Zent, R, Falk, JR, Capdevila, JH Charaterization of 5,6-and 8,9-Epoxyeicosatrienoic acids (5,6- AND 8,9-EET) as potent in vivo angiogenic lipids J Biol Chem 2005. :

» Br?!bek, J, Constancio, SS, Siesser, PF, Shin, NY, Pozzi, A, Hanks, SK Crk-associated substrate tyrosine phosphorylation sites are critical for invasion and metastasis of SRC-transformed cells Mol Cancer Res 2005. 3:307-15

» Thomas, EK, Nakamura, M, Wienke, D, Isacke, CM, Pozzi, A, Liang, P Endo180 binds to the C-terminal region of alpha 1(I) collagen J Biol Chem 2005. :

» Chen, X, Su, Y, Fingleton, B, Acuff, H, Matrisian, LM, Zent, R, Pozzi, A An orthotopic model of lung cancer to analyze primary and metastatic NSCLC growth in integrin alpha1-null mice Clin Exp Metastasis 2005. 22:185-93

» Chen, X, Su, Y, Fingleton, B, Acuff, H, Matrisian, LM, Zent, R, Pozzi, A Increased plasma MMP9 in integrin alpha1-null mice enhances lung metastasis of colon carcinoma cells Int J Cancer 2005. 116:52-61

» Chen, X, Moeckel, G, Morrow, JD, Cosgrove, D, Harris, RC, Fogo, AB, Zent, R, Pozzi, A Lack of integrin alpha1beta1 leads to severe glomerulosclerosis after glomerular injury Am J Pathol 2004. 165:617-30

» Pozzi, A, Yan, X, Macias-Perez, I, Wei, S, Hata, AN, Breyer, RM, Morrow, JD, Capdevila, JH Colon carcinoma cell growth is associated with prostaglandin E2/EP4 receptor-evoked ERK activation J Biol Chem 2004. 279:29797-804

» Br?!bek, J, Constancio, SS, Shin, NY, Pozzi, A, Weaver, AM, Hanks, SK CAS promotes invasiveness of Src-transformed cells Oncogene 2004. 23:7406-15

» Brantley-Sieders, DM, Caughron, J, Hicks, D, Pozzi, A, Ruiz, JC, Chen, J EphA2 receptor tyrosine kinase regulates endothelial cell migration and vascular assembly through phosphoinositide 3-kinase-mediated Rac1 GTPase activation J Cell Sci 2004. 117:2037-49

» Chen, D, Roberts, R, Pohl, M, Nigam, S, Kreidberg, J, Wang, Z, Heino, J, Ivaska, J, Coffa, S, Harris, RC, Pozzi, A, Zent, R Differential expression of collagen- and laminin-binding integrins mediates ureteric bud and inner medullary collecting duct cell tubulogenesis Am J Physiol Renal Physiol 2004. 287:F602-11

» Ma, LJ, Jha, S, Ling, H, Pozzi, A, Ledbetter, S, Fogo, AB Divergent effects of low versus high dose anti-TGF-beta antibody in puromycin aminonucleoside nephropathy in rats Kidney Int 2004. 65:106-15

» Moeckel, GW, Zhang, L, Fogo, AB, Hao, CM, Pozzi, A, Breyer, MD COX2 activity promotes organic osmolyte accumulation and adaptation of renal medullary interstitial cells to hypertonic stress J Biol Chem 2003. 278:19352-7

» Pozzi, A, Zent, R Integrins: sensors of extracellular matrix and modulators of cell function Nephron Exp Nephrol 2003. 94:e77-84

» Pozzi, A, LeVine, WF, Gardner, HA Low plasma levels of matrix metalloproteinase 9 permit increased tumor angiogenesis Oncogene 2002. 21:272-81

» Brantley, DM, Cheng, N, Thompson, EJ, Lin, Q, Brekken, RA, Thorpe, PE, Muraoka, RS, Cerretti, DP, Pozzi, A, Jackson, D, Lin, C, Chen, J Soluble Eph A receptors inhibit tumor angiogenesis and progression in vivo Oncogene 2002. 21:7011-26

» Rose D.M., A. Pozzi, and R. Zent Integrins as Therapeutic targets. Emerging Therapeutic Target 2000. 4:387-411

» Pozzi A, Moberg PE, Miles LA, Wagner S, Soloway P, Gardner HA Elevated matrix metalloprotease and angiostatin levels in integrin alpha 1 knockout mice cause reduced tumor vascularization Proc Natl Acad Sci U S A 2000. 97:2202-7

» Giannelli G, Pozzi A, Stetler-Stevenson WG, Gardner HA, Quaranta V Expression of matrix metalloprotease-2-cleaved laminin-5 in breast remodeling stimulated by sex steroids Am J Pathol 1999. 154:1193-201

» Gardner H, Broberg A, Pozzi A, Laato M, Heino J Absence of integrin alpha1beta1 in the mouse causes loss of feedback regulation of collagen synthesis in normal and wounded dermis J Cell Sci. 1999. 112:263-72

» Pozzi A, Wary KK, Giancotti FG, Gardner HA Integrin alpha1beta1 mediates a unique collagen- dependent proliferation pathway in vivo J Cell Biol 1998. 142:587-94

» Pozzi A, Risek B, Kiang DT, Gilula NB, Kumar NM Analysis of multiple gap junction gene products in the rodent and human mammary gland Exp Cell Res 1995. 220:212-9