Center for Matrix Biology - Vanderbilt University and Medical Center

Mary M. Zutter, M.D.
Professor in the Department of Pathology

	Office Address:	C2102 MCN
	Mailing Address:	C2102 MCN Nashville, TN 2651
	Lab address:	C2102 MCN
	Phone:	615-322-0146
		email

Secondary appointment in the Cancer Biology department.
Secondary appointment in the Microbiology and Immunology department.

Research Summary

Our laboratory focuses on the molecular basis of cell adhesion to collagen an its role in cancer biology. Much of the effort has been centered on the a2a1 integrin. The a2a1 integrin, a receptor for collagens, laminins, decorin, E-cadherin, matrix metalloproteinase-1 (MMP-1), endorepellin, and several viruses, has been implicated in normal developmental, inflammatory, and oncogenic processes. We demonstrated that although a2a1 integrin is highly expressed in epithelium of normal mammary gland, a2a1 integrin expression is lost in a manner that correlated with tumor progression. Much of our early work focused on the molecular mechanism by which the a2a1 integrin mediates branching morphogenesis. We use cell and molecular biology, mouse models of cancer, and organotypic model systems to address questions in cancer biology, immunology, and hemostasis.

1. The a2a1 integrin: a regulator of breast cancer metastasis.

The a2a1 integrin is expressed at high levels by most normal epithelial cells. In many epithelial malignancies a2a1 integrin expression is diminished or lost in a manner that correlates with the loss of epithelial differentiation and tumor progression. To characterize the role of the a2a1 integrin in tumor biology we utilized genetically engineered mice (GEM) in which expression of the a2a1 integrin is completely eliminated either in the entire animal or in mammary epithelial cells. To determine the effect of a2a1 integrin-deficiency on breast cancer initiation, growth, progression, and metastasis we intercrossed the a2a1 integrin-deficient mouse with MMTV-c-neu mice to generate wild type/MMTV-c-neu (WT/c-neu) and a2-null/MMTV-c-neu (a2-null/c-neu). There was no difference in tumor incidence or tumor latency. The rate of tumor growth was also similar in the wild-type and the a2-null animals (P=0.47). Although tumor incidence and growth were not significantly different, the number and size of metastatic foci was significantly different. Animals lacking the a2a1 integrin developed a significantly higher number of lung metastases and larger metastatic foci compared to the wild-type mice. These data suggest that in this model the a2a1 integrin functions as a metastasis suppressor. In the generation of these animals, the a2a1 integrin was deleted globally in all cells of the animal. Although, the contribution of a2a1 integrin expression to metastasis suppression is clear, these data raise important questions which are the focus of ongoing work in the laboratory to dissect the molecular mechanisms by which a2a1 integrin suppresses the metastatic phenotype. Studies are ongoing to define the role of the integrin expression or lack thereof on the tumor cells alone, on cells within the host microenvironment alone, or the contribution on both the tumor cells and within the host microenvironment in tumor metastasis.

2. The a2a1 integrin and the innate immune response/

The a2a1 integrin is expressed on activated T lymphocytes, natural killer cells, other inflammatory cells, and mast cells. We have recently discovered that the a2a1 integrin is a novel receptor for multiple collectins and the C1q complement protein and is required for the innate immune response. The a2a1 integrin provides a co-stimulatory signal required for mast cell activation, cytokine secretion and initiation of innate immunity. We recently demonstrated that crosstalk between c-met and the a2a1 integrin contributes to mast-cell activation in autoimmune and inflammatory disorders. Ongoing projects are directed toward understanding the role that the a2a1 integrin plays in immune modulation in diseases such as arthritis and asthma.

Research Keywords

Cancer, Developmental biology, Immunology, Knockout, Malignancy, Mouse, Pathology, Vascular Biology,

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Associated initiative(s):

Angiogenesis

Tissue Regeneration

Tumor Microenvironment

Career opportunities:
None currently available

Selected Publications

» 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

» McCall-Culbreath, KD, Zutter, MM Collagen receptor integrins: rising to the challenge Curr Drug Targets 2008. 9:139-49

» McCall-Culbreath, KD, Li, Z, Zutter, MM Crosstalk between the alpha2beta1 integrin and c-met/HGF-R regulates innate immunity Blood 2008. 111:3562-70

» Grenache, DG, Zhang, Z, Wells, LE, Santoro, SA, Davidson, JM, Zutter, MM Wound healing in the alpha2beta1 integrin-deficient mouse: altered keratinocyte biology and dysregulated matrix metalloproteinase expression J Invest Dermatol 2007. 127:455-66

» Zutter, MM Integrin-mediated adhesion: tipping the balance between chemosensitivity and chemoresistance Adv Exp Med Biol 2007. 608:87-100

» Zutter, MM, Edelson, BT The alpha2beta1 integrin: a novel collectin/C1q receptor Immunobiology 2007. 212:343-53

» Maginnis, MS, Forrest, JC, Kopecky-Bromberg, SA, Dickeson, SK, Santoro, SA, Zutter, MM, Nemerow, GR, Bergelson, JM, Dermody, TS Beta1 integrin mediates internalization of mammalian reovirus J Virol 2006. 80:2760-2770

» Edelson, BT, Stricker, TP, Li, Z, Dickeson, SK, Shepherd, VL, Santoro, SA, Zutter, MM Novel collectin/C1q receptor mediates mast cell activation and innate immunity Blood 2006. 107:143-156

» Edelson, BT, Stricker, TP, Li, Z, Dickeson, SK, Shepherd, VL, Santoro, SA, Zutter, MM Novel collectin/C1q receptor mediates mast cell activation and innate immunity Blood 2006. 107:143-50

» Sarratt, KL, Chen, H, Zutter, MM, Santoro, SA, Hammer, DA, Kahn, ML GPVI and alpha2beta1 play independent critical roles during platelet adhesion and aggregate formation to collagen under flow Blood 2005. 106:1268-77

» Zutter, MM, Santoro, SA Widespread histologic distribution of the a2b1 integin cell surface collagan receptor Am J Pathol 2004. 137:113-120

» Edelson, BT, Li, Z, Pappan, LK, Zutter, MM Mast cell-mediated inflammatory responses require the a2b1 integrin Blood 2004. 103:2214-2220

» Bix, G, Fu, J, Gonzalez, EM, Macro, L, Barker, A, Campbell, S, Zutter, MM, Santoro, SA, Kim, JK, H????k, M, Reed, CC, Iozzo, RV Endorepellin causes endothelial cell disassembly of actin cytoskeleton and focal adhesions through alpha2beta1 integrin J Cell Biol 2004. 166:97-109

» DeClerck, YA, Mercurio, AM, Stack, MS, Chapman, HA, Zutter, MM, Muschel, RJ, Raz, A, Matrisian, LM, Sloane, BF, Noel, A, Hendrix, MJ, Coussens, L, Padarathsingh, M Proteases, extracellular matrix, and cancer: a workshop of the path B study section Am J Pathol 2004. 164:1131-9

» Edelson, BT, Li, Z, Pappan, LK, Zutter, MM Mast cell-mediated inflammatory responses require the alpha 2 beta 1 integrin Blood 2004. 103:2214-20

» He, Li, Pappan, Loretta K, Grenache, David G, Li, Zhengzhi, Tollefsen, Douglas M, Santoro, Samuel A, Zutter, Mary M The contributions of the I?2I?1 integrin to vascular thrombosis in vivo Blood 2003. 102:3652-3657

» Grenache, DG, Coleman, T, Semenkovich, CF, santoro, SA, Zutter, MM a2b1 integrin and development of atheroscierosis in a mouse model: Assessment of risk Arteriosclerosis, Thombois, and Vascular Biology 2003. 23:2104-2109

» Grenache, DG, Coleman, T, Semenkovich, CF, Santoro, SA, Zutter, MM Alpha2beta1 integrin and development of atherosclerosis in a mouse model: assessment of risk Arterioscler Thromb Vasc Biol 2003. 23:2104-9

» Chen, Jianchun, Diacovo, Thomas G, Grenache, David G, Santoro, Samuel A, Zutter, Mary M The alpha(2) integrin subunit-deficient mouse: a multifaceted phenotype including defects of branching morphogenesis and hemostasis Am J Pathol 2002. 161:337-344

» Klekotka, PA, Santoro, SA, Ho, A, Dowdy, SF, Zutter, MM Mammary epithelial cell-cycle progression via the alpha(2)beta(1) integrin: unique and synergistic roles of the alpha(2) cytoplasmic domain Am J Pathol 2001. 159:983-992

» Kaleem, Z, White, G, Zutter, MM Aberrant expression of T-cell-associated antigens on B-cell non-Hodgkin lymphomas Am J Clin Pathol 2001. 115:396-403

» Klekotka, P A, Santoro, S A, Wang, H, Zutter, M M, Specific residues within the alpha 2 integrin subunit cytoplasmic domain regulate migration and cell cycle progression via distinct MAPK pathways. J Biol Chem 2001. 276:32353-61

» Klekotka, PA, Santoro, SA, Zutter, MM alpha 2 integrin subunit cytoplasmic domain-dependent cellular migration requires p38 MAPK J Biol Chem 2001. 276:9503-11

» Klekotka, PA, Santoro, SA, Zutter, MM a2 integrin subunit cytoplasmic domain dependent cellular migration requiresp38 MAPK J Biol Chem 2001. 276:9503-9511

» Wang, H, Gai, Q, Yang, X, Li, Z, Linders, B, Santoro, SA, Zutter, MM Role of the alpha1 and alpha2 integrin cytoplasmic domains in cell morphology, motility and responsiveness to stimulation by the protein kinase C pathway Cell Adhes Commun 2000. 7:281-97

» O''Sullivan, MJ, Kaleem, Z, Bolger, MJ, Swanson, PE, Zutter, MM Composite prolymphocytoid and hodgkin transformation of chronic lymphocytic leukemia Arch Pathol Lab Med 2000. 124:907-9

» Kaleem, Z, Shuster, JJ, Carroll, AJ, Borowitz, MJ, Pullen, DJ, Camitta, BM, Zutter, MM, Watson, MS Acute lymphoblastic leukemia with an unusual t(8;14)(q11.2;q32): a Pediatric Oncology Group Study Leukemia 2000. 14:238-40

» Wang, H, Gai, Q, Yang, X, Li, Z, Linders, B, Santoro, S, Zutter, M Role of the a1 and a2 integrin cytoplasmic domains in cell morphology, motility and responsiveness to stimulation by the protein kinase C pathway Cell Adhesion and Communication 2000. 74:281-297

» Kaleem, Z, Zehnbauer, BA, White, G, Zutter, MM Lack of expression of surface immunoglobulin light chains in B-cell non-Hodgkin lymphomas Am J Clin Pathol 2000. 113:399-405

» Zutter, MM, Santoro, SA, Wu, JE, Wakatsuki, T, Dickeson, SK, Elson, E Collagen receptor control of epithelial morphogenesis and cell cycle progression Am J Path 1999. 155:927-940

» Kaleem, Z, Watson, MS, Zutter, MM, Blinder, MA, Hess, JL Acute promyelocytic leukemia with additional chromosomal abnormalities and absence of Auer rods Am J Clin Pathol 1999. 112:113-8

» Zutter, MM, Santoro, SA, Wu, JE, Wakatsuki, T, Dickeson, SK, Elson, EL Collagen receptor control of epithelial morphogenesis and cell cycle progression Am J Pathol 1999. 155:927-40

» Zutter, MM, Painter, AD, Yang, X The megakaryocyte/platelet-specific enhancer of the a2b1 integrin gene: Two tandem AP1 sites and the mitogen activated protein kinase signaling cascade Blood 1999. 93:1600-1611

» Zutter, MM, Painter, AD, Yang, X The Megakaryocyte/Platelet-specific enhancer of the alpha2beta1 integrin gene: two tandem AP1 sites and the mitogen-activated protein kinase signaling cascade Blood 1999. 93:1600-11

» Zutter, MM, Sun, H, Santoro, SA Altered integrin expression and the malignant phenotype: the contribution of multiple integrated integrin receptors J Mammary Gland Biol Neoplasia 1998. 3:191-200

» Zutter, MM, Hess, JL Guidelines for the diagnosis of leukemia or lymphoma in children Am J Clin Pathol 1998. 109:S9-22

» Zutter, MM Gastrointestinal carcinoma antigen GA733: target for immunodestruction and potential modifier of invasiveness and chemoresponsiveness J Natl Cancer Inst 1998. 90:642-4

» Xu, J, Zutter, MM, Santoro, SA, Clark, RA A three-dimensional collagen lattice activates NF-kappaB in human fibroblasts: role in integrin alpha2 gene expression and tissue remodeling J Cell Biol 1998. 140:709-19

» Zutter, MM, Sun, H, Santoro, SA Altered integrin expression and the malignant phenotype: the contribution of multiple integrated integrin-derived influences J Mam Gland Biol and Neo 1998. 3(2):191-200

» Xu, J, Zutter, MM, Santoro, SA, Clark, RAF A three dimensional collagen lattice ctivates NF-kB in human fibroblasts: role in integrin a2 gene expression and tissue remodeling J Cell Biol 1998. 140:709-719

» Zutter, MM, Santoro, SA The ups and downs of alpha 2 beta 1-integrin expression: contributions to epithelial cell differentiation and the malignant phenotype Curr Top Microbiol Immunol 1998. 231:167-85

» Naughton, MJ, Hess, JL, Zutter, MM, Bartlett, NL Bone marrow staging in patients with non-Hodgkin''s lymphoma: is flow cytometry a useful test Cancer 1998. 82:1154-9

» Sun, H, Santoro, SA, Zutter, MM Downstream events in mammary gland morphogenesis mediated by reexpression of the alpha2beta1 integrin: the role of the alpha6 and beta4 integrin subunits Cancer Res 1998. 58:2224-33

» Hong, S, Santoro, SA, Zutter, MM Down-stream events in mammary gland morphogenesis mediated by re-expression of the a2b1 integrin: the role of the a6 and b4 integrin subunits Cancer Research 1998. 58:2224-2233

» Zutter, MM, Ryan, EE, Painter, AD Binding of phosphorylated Sp1 protein to tandem Sp1 binding sites regulates a2 integrin gene core promoter activity Blood 1997. 90:678-689

» Tachibana, I, Bodorova, J, Berditchevski, F, Zutter, MM, Hemler, ME NAG-2, a novel transmembrane-4 superfamily (TM4SF) protein that complexes with integrins and other TM4SF proteins J Biol Chem 1997. 272:29181-9

» Zutter, MM, Ryan, EE, Painter, AD Binding of phosphorylated Sp1 protein to tandem Sp1 binding sites regulates alpha2 integrin gene core promoter activity Blood 1997. 90:678-89

» Berditchevski, F, Zutter, MM, Hemler, ME Characterization of novel complexes on the cell surface between integrins and proteins with 4 transmembrane domains (TM4 proteins) Mol Biol Cell 1996. 7:193-207

» Hess, JL, Zutter, MM, Castleberry, RP, Emanuel, PD Juvenile chronic myelogenous leukemia Am J Clin Pathol 1996. 105:238-48

» Xu, J, Zutter, MM, Santoro, SA, Clark, RA PDGF induction of alpha 2 integrin gene expression is mediated by protein kinase C-zeta J Cell Biol 1996. 134:1301-11

» Clatch, RJ, Walloch, JL, Zutter, MM, Kamentsky, LA Immunophenotypic analysis of hematologic malignancy by laser scanning cytometry Am J Clin Pathol 1996. 105:744-55

» Zutter, MM, Santoro, SA, Staatz, WD, Tsung, YL Re-expression of the a2b1 integrin abrogates the malignant phenotype of breast carcinoma cells Proc Natl Acad Sci USA 1995. 92:7411-7415

» Santoro, SA, Zutter, MM A collagen receptor on platelets and other cells Thromb Haemostas 1995. 74:813-821

» Zutter, MM, Painter, AD, Staatz, WD, Tsung, YL Regulation of a2 integrin gene espression during megakaryocte differentiation: A common theme of three necessary elements for megakaryocyte-specific, developmentally regulated gene expression Blood 1995. 86:3006-3014

» Grossman, WJ, Kimata, JT, Wong, FH, Zutter, MM, Ley, T, Ratner, L Development of leukemia in mice transgenic for the Tax gene of human T-cell leukemia virus Type 1 Proc Natl Acad Sci USA 1995. 92:1057-1061

» Keely, PJ, Fong, AM, Zutter, MM, Santoro, SA Alteration of collagen-dependent adhesion, motility, and morphogenesis by the expression of antisense a2 integrin mRNA in mammary cells J Cell Science 1995. 108:595-607

» Keely, PJ, Fong, AM, Zutter, MM, Santoro, SA Alteration of collagen-dependent adhesion, motility, and morphogenesis by the expression of antisense alpha 2 integrin mRNA in mammary cells J Cell Sci 1995. 108 ( Pt 2):595-607

» Zutter, MM, Santoro, SA, Staatz, WD, Tsung, YL Re-expression of the alpha 2 beta 1 integrin abrogates the malignant phenotype of breast carcinoma cells Proc Natl Acad Sci U S A 1995. 92:7411-5

» Santoro, SA, Zutter, MM The alpha 2 beta 1 integrin: a collagen receptor on platelets and other cells Thromb Haemost 1995. 74:813-21

» Zutter, MM, Painter, AA, Staatz, WD, Tsung, YL Regulation of alpha 2 integrin gene expression in cells with megakaryocytic features: a common theme of three necessary elements Blood 1995. 86:3006-14

» Santoro, SA, Zutter, MM, Wu, JE, Staatz, WD, Saelman, EU, Keely, PJ Analysis of collagen receptors Methods Enzymol 1994. 245:147-83

» Clatch, RJ, Krigman, HR, Peters, MG, Zutter, MM Dysplastic haemopoiesis following orthotopic liver transplantation: comparison with similar changes in HIV infection and primary myelodysplasia Br J Haematol 1994. 88:685-92

» Zutter, MM, Santoro, SA, Painter, AS, Tsung, YL, Gafford, A Identification of positive and negative regulatory elements important in cell-type and developmentally-restricted gene expression J Biol Chem 1994. 269:463-469

» Zutter, MM, Santoro, SA, Painter, AS, Tsung, YL, Gafford, A The human alpha 2 integrin gene promoter. Identification of positive and negative regulatory elements important for cell-type and developmentally restricted gene expression J Biol Chem 1994. 269:463-9

» Zutter, MM, Krigman, HR, Santoro, SA Altered integrin expression in adenocarcinoma of the breast: Analysis by in situ hybridization Am J Pathol 1993. 142:1439-1448

» Lentz, SR, Krewson, L, Zutter, MM Recurrent neuroendocrine (Merkel cell) carcinoma of the skin presenting as marrow failure in a man with systemic lupus erythematosus Med Pediatr Oncol 1993. 21:137-41

» Zutter, MM, Krigman, HR, Santoro, SA Altered integrin expression in adenocarcinoma of the breast. Analysis by in situ hybridization Am J Pathol 1993. 142:1439-48

» Kaufman, BA, Jones, L, Zutter, MM, Park, TS Megakaryoblastic leukemia presenting as a temporal bone granulocytic sarcoma. Case report J Neurosurg 1993. 79:128-31

» Zutter, MM, Fong, AF, Krigman, HR, Santoro, SA Differential regulation of the a(2)b(1) and a(IIb)b(3) integrin genes during megakaryocytic differentiation of pluripotent K562 leukemia cells J Biol Chem 1992. 267:20233-20238

» Zutter, MM, Fong, AM, Krigman, HR, Santoro, SA Differential regulation of the alpha 2 beta 1 and alpha IIb beta 3 integrin genes during megakaryocytic differentiation of pluripotential K562 cells J Biol Chem 1992. 267:20233-8

» Pacifici, R, Basilico, C, Roman, J, Zutter, MM, Santoro, SA, McCracken, R Collagen-induced release of interleukin 1 from human blood mononuclear cells. Potentiation by fibronectin binding to the alpha 5 beta 1 integrin J Clin Invest 1992. 89:61-7

» Burger, SR, Zutter, MM, Sturgill-Koszycki, S, Santoro, SA Induced cell surface expression of functional alpha 2 beta 1 integrin during megakaryocytic differentiation of K562 leukemic cells Exp Cell Res 1992. 202:28-35

» Zutter, MM The immunolocalization of integrin receptors in normal lymphoid tissues Blood 1991. 77:2231-2236

» Gratama, JW, Zutter, MM, Minarovits, J, Oosterveer, MA, Thomas, ED, Klein, G, Ernberg, I Expression of Epstein-Barr virus-encoded growth-transformation-associated proteins in lymphoproliferations of bone-marrow transplant recipients Int J Cancer 1991. 47:188-92

» Staatz, WD, Fok, KF, Zutter, MM, Adams, SP, Rodriguez, BA, Santoro, SA Identification of a tetrapeptide recognition sequence for the alpha 2 beta 1 integrin in collagen J Biol Chem 1991. 266:7363-7

» Zutter, MM Immunolocalization of integrin receptors in normal lymphoid tissues Blood 1991. 77:2231-6

» Hockenbery, D, Zutter, MM, Hickey, W., Nahm, M., Korsmeyer, SJ Bcl-2 protein expression is topographically restricted in tissue characterized by apoptotic cell death Proc Natl Acad Sci USA 1991. 88:6961-6965

» Zutter, MM, Gersell, DJ Acute lymphoblastic leukemia. An unusual case of primary relapse in the uterine cervix Cancer 1990. 66:1002-4

» Zutter, MM, Santoro, SA Widespread histologic distribution of the alpha 2 beta 1 integrin cell-surface collagen receptor Am J Pathol 1990. 137:113-20

» Zutter, MM, Mazoujian, G, Santoro, SA Decreased expression of integrin adhesive protein receptors in adenocarcinoma of the breast Am J Pathol 1990. 137:863-70

» Atlas, AB, Manthei, U, Zutter, MM, Polmar, SH Necrotizing granulomatosis of the spleen in chronic granulomatous disease Am J Dis Child 1990. 144:14-5

» Zutter, MM, Martin, PJ, Hanke, D, Kidd, PG CD7+ acute non-lymphocytic leukemia: evidence for an early multipotential progenitor Leuk Res 1990. 14:23-6

» Zutter, MM, Mazoujian, G., Santoro, SA Decreased expression of integrin adhesive protein receptors in adenocarcinoma of the breast Am J Pathol 1990. 137:863-870

» Zutter, MM, Durnam, DM, Hackman, RC, Loughran, TP, Kidd, PG, Ashley, RL, Petersdorf, EW, Martin, PJ, Thomas, ED Secondary T-cell lymphoproliferation after marrow transplantation Am J Clin Pathol 1990. 94:714-21

» Zutter, MM, Martin, PJ, Sale, GE, Shulman, HM, Fisher, L, Thomas, ED, Durnam, DM Epstein-Barr virus lymphoproliferation after bone marrow transplantation Blood 1988. 72:520-9