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Department of Pathology, Microbiology, and Immunology

 

 

  Mary M. Zutter, M.D.

 

 

Assistant Vice Chancellor for Integrative Diagnostics

Louise B. McGavock Professor of Pathology, Microbiology and Immunology

Professor of Pathology, Microbiology and Immunology
Professor of Cancer Biology

Director, Tumor-Host Interaction Program, Vanderbilt Ingram Cancer Center

 

 

  Contact Information

 

 

Office Location:

T-3218B MCN  

Phone: 615.343.1095

Fax: 615.875-1717

E-Mail: mary.zutter@vanderbilt.edu

 

Campus Mail address:

Pathology, Microbiology and Immunology -3rd Fl

C-3321 MCN (2561)

 

US Mailing address:

Vanderbilt University School of Medicine

Pathology, Microbiology and Immunology -3rd Fl

C-3321 MCN

Nashville, TN 37232-2561  

 

 

 

Education

 

 

M.D., Tulane Univ
B.S., Tulane Univ

 

 

Research Keywords

 

 

Integrin, cell adhesion, tumor biology, tumor-host interactions, endothelial and epithelial morphogenesis, innate immunity, mast cells, angiogenesis, metastasis

 

 

Research Description

 

 

Cancer progression involves fundamental alterations of cell-cell and cell-matrix interactions and the cues derived from them that contribute to the invasive and metastatic phenotype. As important mediators of cell adhesive behavior, integrins play a critical role in tumor progression and metastasis. Their role in mediating adhesion to either components of the extracellular matrix or to other cells is now well established.

Our laboratory focuses on the molecular basis of cell adhesion to collagen with a focus on the I?2I?1 integrin. The I?2I?1 integrin, a receptor for collagens, laminins, decorin, E-cadherin, as well as other ligands, has been implicated in normal developmental, inflammatory, and oncogenic processes. 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 I?2I?1 integrin: a regulator of breast cancer metastasis.

The I?2I?1 integrin is expressed at high levels by most normal epithelial cells. In many epithelial malignancies I?2I?1 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 I?2I?1 integrin in tumor biology we utilized genetically engineered mice (GEM) in which expression of the I?2I?1 integrin is completely eliminated. Early studies provided the initial correlative suggestion that loss of I?2I?1 integrin expression might play an important role in cancer progression. Alternatively, loss of I?2I?1 integrin expression may simply be a consequence of malignant progression. In other studies, however, using cell lines either in vivo or in vitro suggest that the I?2I?1 integrin may serve to enhance metastasis to different organs.
The results of in vitro and in vivo studies of various designs may be subject to conflicting interpretation. Therefore, we have explored the role of the I?2I?1 integrin in cancer initiation and progression using a clinically-relevant, spontaneous mouse model, the MMTV-Neu model of breast cancer progression and metastasis. Furthermore, we have validated and extended the conclusions of our model system with a detailed analysis of I?2 integrin gene expression and its significance in human breast and prostate cancer. We demonstrate that the I?2I?1 integrin is a metastasis suppressor of breast cancer and we identify key mechanistic steps in the metastatic cascade enhanced by loss of I?2I?1 integrin expression.
Although, the contribution of I?2I?1 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 I?2I?1 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 I?2I?1 integrin and the innate immune response

The I?2I?1 integrin is expressed on activated T lymphocytes, natural killer cells, other inflammatory cells, and mast cells. We have recently discovered that the I?2I?1 integrin is a novel receptor for multiple collectins and the C1q complement protein and is required for the innate immune response. The I?2I?1 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/hepatocyte growth factor receptor and the I?2I?1 integrin contributes to mast-cell activation. Ongoing projects are directed toward understanding the role that the I?2I?1 integrin plays in immune modulation in the tumor microenvironment.


 

 

Clinical Research Description

 

 

 

 

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, 111(4), 1980-8, 2008

McCall-Culbreath, KD, Zutter, MM. Collagen receptor integrins: rising to the challenge. Curr Drug Targets, 9(2), 139-49, 2008

McCall-Culbreath, KD, Li, Z, Zutter, MM. Crosstalk between the alpha2beta1 integrin and c-met/HGF-R regulates innate immunity. Blood, 111(7), 3562-70, 2008

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, 127(2), 455-66, 2007

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

Zutter, MM, Edelson, BT. The alpha2beta1 integrin: a novel collectin/C1q receptor. Immunobiology, 212(4-5), 343-53, 2007

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, 80(6), 2760-2770, 2006

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, 107, 143-156, 2006

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, 107(1), 143-50, 2006

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, 106(4), 1268-77, 2005

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

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

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, 166(1), 97-109, 2004

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, 164(4), 1131-9, 2004

Edelson, BT, Li, Z, Pappan, LK, Zutter, MM. Mast cell-mediated inflammatory responses require the alpha 2 beta 1 integrin. Blood, 103(6), 2214-20, 2004

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, 102(10), 3652-3657, 2003

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, 23, 2104-2109, 2003

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, 23(11), 2104-9, 2003

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, 161, 337-344, 2002

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, 159, 983-992, 2001

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

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, 276, 32353-61, 2001

Klekotka, PA, Santoro, SA, Zutter, MM. alpha 2 integrin subunit cytoplasmic domain-dependent cellular migration requires p38 MAPK. J Biol Chem, 276(12), 9503-11, 2001

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

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, 7(4), 281-97, 2000

O''Sullivan, MJ, Kaleem, Z, Bolger, MJ, Swanson, PE, Zutter, MM. Composite prolymphocytoid and hodgkin transformation of chronic lymphocytic leukemia. Arch Pathol Lab Med, 124(6), 907-9, 2000

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, 14(2), 238-40, 2000

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, 74, 281-297, 2000

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, 113(3), 399-405, 2000

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, 155, 927-940, 1999

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, 112(1), 113-8, 1999

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, 155(3), 927-40, 1999

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, 93, 1600-1611, 1999

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, 93(5), 1600-11, 1999

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, 3(2), 191-200, 1998

Zutter, MM, Hess, JL. Guidelines for the diagnosis of leukemia or lymphoma in children. Am J Clin Pathol, 109(4 Suppl 1), S9-22, 1998

Zutter, MM. Gastrointestinal carcinoma antigen GA733: target for immunodestruction and potential modifier of invasiveness and chemoresponsiveness. J Natl Cancer Inst, 90(9), 642-4, 1998

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, 140(3), 709-19, 1998

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, 3(2), 191-200, 1998

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, 140, 709-719, 1998

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, 231, 167-85, 1998

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, 82(6), 1154-9, 1998

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, 58(10), 2224-33, 1998

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, 58, 2224-2233, 1998

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

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, 272(46), 29181-9, 1997

Zutter, MM, Ryan, EE, Painter, AD. Binding of phosphorylated Sp1 protein to tandem Sp1 binding sites regulates alpha2 integrin gene core promoter activity. Blood, 90(2), 678-89, 1997

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, 7(2), 193-207, 1996

Hess, JL, Zutter, MM, Castleberry, RP, Emanuel, PD. Juvenile chronic myelogenous leukemia. Am J Clin Pathol, 105(2), 238-48, 1996

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, 134(5), 1301-11, 1996

Clatch, RJ, Walloch, JL, Zutter, MM, Kamentsky, LA. Immunophenotypic analysis of hematologic malignancy by laser scanning cytometry. Am J Clin Pathol, 105(6), 744-55, 1996

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, 92, 7411-7415, 1995

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

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, 86, 3006-3014, 1995

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, 92, 1057-1061, 1995

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, 108, 595-607, 1995

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, 108 ( Pt 2), 595-607, 1995

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, 92(16), 7411-5, 1995

Santoro, SA, Zutter, MM. The alpha 2 beta 1 integrin: a collagen receptor on platelets and other cells. Thromb Haemost, 74(3), 813-21, 1995

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, 86(8), 3006-14, 1995

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

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, 88(4), 685-92, 1994

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, 269, 463-469, 1994

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, 269(1), 463-9, 1994

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

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, 21(2), 137-41, 1993

Zutter, MM, Krigman, HR, Santoro, SA. Altered integrin expression in adenocarcinoma of the breast. Analysis by in situ hybridization. Am J Pathol, 142(5), 1439-48, 1993

Kaufman, BA, Jones, L, Zutter, MM, Park, TS. Megakaryoblastic leukemia presenting as a temporal bone granulocytic sarcoma. Case report. J Neurosurg, 79(1), 128-31, 1993

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, 267, 20233-20238, 1992

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, 267(28), 20233-8, 1992

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, 89(1), 61-7, 1992

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, 202(1), 28-35, 1992

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

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, 47(2), 188-92, 1991

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, 266(12), 7363-7, 1991

Zutter, MM. Immunolocalization of integrin receptors in normal lymphoid tissues. Blood, 77(10), 2231-6, 1991

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, 88, 6961-6965, 1991

Zutter, MM, Gersell, DJ. Acute lymphoblastic leukemia. An unusual case of primary relapse in the uterine cervix. Cancer, 66(5), 1002-4, 1990

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

Zutter, MM, Mazoujian, G, Santoro, SA. Decreased expression of integrin adhesive protein receptors in adenocarcinoma of the breast. Am J Pathol, 137(4), 863-70, 1990

Atlas, AB, Manthei, U, Zutter, MM, Polmar, SH. Necrotizing granulomatosis of the spleen in chronic granulomatous disease. Am J Dis Child, 144(1), 14-5, 1990

Zutter, MM, Martin, PJ, Hanke, D, Kidd, PG. CD7+ acute non-lymphocytic leukemia: evidence for an early multipotential progenitor. Leuk Res, 14(1), 23-6, 1990

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

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, 94(6), 714-21, 1990

Zutter, MM, Martin, PJ, Sale, GE, Shulman, HM, Fisher, L, Thomas, ED, Durnam, DM. Epstein-Barr virus lymphoproliferation after bone marrow transplantation. Blood, 72(2), 520-9, 1988