Department of Pathology, Microbiology, and Immunology
Assistant Vice Chancellor for Integrative Diagnostics
Professor of Pathology, Microbiology and Immunology
Professor of Cancer Biology
Director, Tumor-Host Interaction Program, Vanderbilt Ingram Cancer Center
Scientific Director, Translational Pathology Shared Resource
Contact Information
Phone: 615.343.1095
Fax: 615.343.7961
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
Education
B.S., Tulane Univ
Research Keywords
Research Description
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
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
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
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
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, 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
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
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, 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
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
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
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, Krigman, HR, Santoro, SA. Altered integrin expression in adenocarcinoma of the breast: Analysis by in situ hybridization. Am J Pathol, 142, 1439-1448, 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. The immunolocalization of integrin receptors in normal lymphoid tissues. Blood, 77, 2231-2236, 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, Mazoujian, G., Santoro, SA. Decreased expression of integrin adhesive protein receptors in adenocarcinoma of the breast. Am J Pathol, 137, 863-870, 1990