Mary Zutter
Faculty Member
Last active: 4/26/2016

Profile

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 ∝2ß1 integrin. The ∝2ß1 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 ∝2ß1 integrin: a regulator of breast cancer metastasis. The ∝2ß1 integrin is expressed at high levels by most normal epithelial cells. In many epithelial malignancies ∝2ß1 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 ∝2ß1 integrin in tumor biology we utilized genetically engineered mice (GEM) in which expression of the ∝2ß1 integrin is completely eliminated. Early studies provided the initial correlative suggestion that loss of ∝2ß1 integrin expression might play an important role in cancer progression. Alternatively, loss of ∝2ß1 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 ∝2ß1 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 ∝2ß1 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 ∝2 integrin gene expression and its significance in human breast and prostate cancer. We demonstrate that the ∝2ß1 integrin is a metastasis suppressor of breast cancer and we identify key mechanistic steps in the metastatic cascade enhanced by loss of ∝2ß1 integrin expression. Although, the contribution of ∝2ß1 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 ∝2ß1 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.

The ∝2ß1 integrin also plays a role in the innate and adaptive immune response. The ∝2ß1 integrin is expressed on activated T lymphocytes, natural killer cells, other inflammatory cells, and mast cells. We have recently discovered that the ∝2ß1 integrin is a novel receptor for multiple collectins and the C1q complement protein and is required for the innate immune response. The ∝2ß1 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 ∝2ß1 integrin contributes to mast-cell activation. Ongoing projects are directed toward understanding the role that the ∝2ß1 integrin plays in immune modulation in the tumor microenvironment.

Publications

The following timeline graph is generated from all co-authored publications.

Featured publications are shown below:

  1. Loss of the α2β1 integrin alters human papilloma virus-induced squamous carcinoma progression in vivo and in vitro. Tran T, Barlow B, O'Rear L, Jarvis B, Li Z, Dickeson K, Dupont W, Zutter M (2011) PLoS One 6(10): e26858
    › Primary publication · 22046385 (PubMed) · PMC3203166 (PubMed Central)
  2. Selective, α2β1 integrin-dependent secretion of il-6 by connective tissue mast cells. McCall-Culbreath KD, Li Z, Zhang Z, Lu LX, Orear L, Zutter MM (2011) J Innate Immun 3(5): 459-70
    › Primary publication · 21502744 (PubMed) · PMC3186713 (PubMed Central)
  3. The α₂β₁ integrin is a metastasis suppressor in mouse models and human cancer. Ramirez NE, Zhang Z, Madamanchi A, Boyd KL, O'Rear LD, Nashabi A, Li Z, Dupont WD, Zijlstra A, Zutter MM (2011) J Clin Invest 121(1): 226-37
    › Primary publication · 21135504 (PubMed) · PMC3007139 (PubMed Central)
  4. Crosstalk between the alpha2beta1 integrin and c-met/HGF-R regulates innate immunity. McCall-Culbreath KD, Li Z, Zutter MM (2008) Blood 111(7): 3562-70
    › Primary publication · 18198349 (PubMed) · PMC2275022 (PubMed Central)
  5. alpha2beta1 integrin expression in the tumor microenvironment enhances tumor angiogenesis in a tumor cell-specific manner. Zhang Z, Ramirez NE, Yankeelov TE, Li Z, Ford LE, Qi Y, Pozzi A, Zutter MM (2008) Blood 111(4): 1980-8
    › Primary publication · 18042800 (PubMed) · PMC2234046 (PubMed Central)
  6. The alpha2beta1 integrin: a novel collectin/C1q receptor. Zutter MM, Edelson BT (2007) Immunobiology 212(4-5): 343-53
    › Primary publication · 17544819 (PubMed)
  7. Beta1 integrin mediates internalization of mammalian reovirus. Maginnis MS, Forrest JC, Kopecky-Bromberg SA, Dickeson SK, Santoro SA, Zutter MM, Nemerow GR, Bergelson JM, Dermody TS (2006) J Virol 80(6): 2760-70
    › Primary publication · 16501085 (PubMed) · PMC1395463 (PubMed Central)
  8. Endorepellin causes endothelial cell disassembly of actin cytoskeleton and focal adhesions through alpha2beta1 integrin. Bix G, Fu J, Gonzalez EM, Macro L, Barker A, Campbell S, Zutter MM, Santoro SA, Kim JK, Höök M, Reed CC, Iozzo RV (2004) J Cell Biol 166(1): 97-109
    › Primary publication · 15240572 (PubMed) · PMC2172143 (PubMed Central)
  9. Proteases, extracellular matrix, and cancer: a workshop of the path B study section. 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 (2004) Am J Pathol 164(4): 1131-9
    › Primary publication · 15039201 (PubMed) · PMC1615345 (PubMed Central)
  10. Mast cell-mediated inflammatory responses require the alpha 2 beta 1 integrin. Edelson BT, Li Z, Pappan LK, Zutter MM (2004) Blood 103(6): 2214-20
    › Primary publication · 14645004 (PubMed)
  11. Alpha2beta1 integrin and development of atherosclerosis in a mouse model: assessment of risk. Grenache DG, Coleman T, Semenkovich CF, Santoro SA, Zutter MM (2003) Arterioscler Thromb Vasc Biol 23(11): 2104-9
    › Primary publication · 14512368 (PubMed)
  12. The contributions of the alpha 2 beta 1 integrin to vascular thrombosis in vivo. He L, Pappan LK, Grenache DG, Li Z, Tollefsen DM, Santoro SA, Zutter MM (2003) Blood 102(10): 3652-7
    › Primary publication · 12893751 (PubMed)
  13. The alpha(2) integrin subunit-deficient mouse: a multifaceted phenotype including defects of branching morphogenesis and hemostasis. Chen J, Diacovo TG, Grenache DG, Santoro SA, Zutter MM (2002) Am J Pathol 161(1): 337-44
    › Primary publication · 12107118 (PubMed) · PMC1850700 (PubMed Central)
  14. Mammary epithelial cell-cycle progression via the alpha(2)beta(1) integrin: unique and synergistic roles of the alpha(2) cytoplasmic domain. Klekotka PA, Santoro SA, Ho A, Dowdy SF, Zutter MM (2001) Am J Pathol 159(3): 983-92
    › Primary publication · 11549591 (PubMed) · PMC1850465 (PubMed Central)
  15. Specific residues within the alpha 2 integrin subunit cytoplasmic domain regulate migration and cell cycle progression via distinct MAPK pathways. Klekotka PA, Santoro SA, Wang H, Zutter MM (2001) J Biol Chem 276(34): 32353-61
    › Primary publication · 11418614 (PubMed)
  16. Aberrant expression of T-cell-associated antigens on B-cell non-Hodgkin lymphomas. Kaleem Z, White G, Zutter MM (2001) Am J Clin Pathol 115(3): 396-403
    › Primary publication · 11242796 (PubMed)
  17. alpha 2 integrin subunit cytoplasmic domain-dependent cellular migration requires p38 MAPK. Klekotka PA, Santoro SA, Zutter MM (2001) J Biol Chem 276(12): 9503-11
    › Primary publication · 11121402 (PubMed)
  18. Composite prolymphocytoid and hodgkin transformation of chronic lymphocytic leukemia. O'Sullivan MJ, Kaleem Z, Bolger MJ, Swanson PE, Zutter MM (2000) Arch Pathol Lab Med 124(6): 907-9
    › Primary publication · 10835534 (PubMed)
  19. Altered integrin expression and the malignant phenotype: the contribution of multiple integrated integrin receptors. Zutter MM, Sun H, Santoro SA (1998) J Mammary Gland Biol Neoplasia 3(2): 191-200
    › Primary publication · 10819527 (PubMed)
  20. Role of the alpha1 and alpha2 integrin cytoplasmic domains in cell morphology, motility and responsiveness to stimulation by the protein kinase C pathway. Wang H, Gai Q, Yang X, Li Z, Linders B, Santoro SA, Zutter MM (2000) Cell Adhes Commun 7(4): 281-97
    › Primary publication · 10714390 (PubMed)
  21. Lack of expression of surface immunoglobulin light chains in B-cell non-Hodgkin lymphomas. Kaleem Z, Zehnbauer BA, White G, Zutter MM (2000) Am J Clin Pathol 113(3): 399-405
    › Primary publication · 10705821 (PubMed)
  22. Acute lymphoblastic leukemia with an unusual t(8;14)(q11.2;q32): a Pediatric Oncology Group Study. Kaleem Z, Shuster JJ, Carroll AJ, Borowitz MJ, Pullen DJ, Camitta BM, Zutter MM, Watson MS (2000) Leukemia 14(2): 238-40
    › Primary publication · 10673739 (PubMed)
  23. Collagen receptor control of epithelial morphogenesis and cell cycle progression. Zutter MM, Santoro SA, Wu JE, Wakatsuki T, Dickeson SK, Elson EL (1999) Am J Pathol 155(3): 927-40
    › Primary publication · 10487850 (PubMed) · PMC1866884 (PubMed Central)
  24. Acute promyelocytic leukemia with additional chromosomal abnormalities and absence of Auer rods. Kaleem Z, Watson MS, Zutter MM, Blinder MA, Hess JL (1999) Am J Clin Pathol 112(1): 113-8
    › Primary publication · 10396293 (PubMed)
  25. The Megakaryocyte/Platelet-specific enhancer of the alpha2beta1 integrin gene: two tandem AP1 sites and the mitogen-activated protein kinase signaling cascade. Zutter MM, Painter AD, Yang X (1999) Blood 93(5): 1600-11
    › Primary publication · 10029589 (PubMed)
  26. Downstream events in mammary gland morphogenesis mediated by reexpression of the alpha2beta1 integrin: the role of the alpha6 and beta4 integrin subunits. Sun H, Santoro SA, Zutter MM (1998) Cancer Res 58(10): 2224-33
    › Primary publication · 9605770 (PubMed)
  27. Gastrointestinal carcinoma antigen GA733: target for immunodestruction and potential modifier of invasiveness and chemoresponsiveness. Zutter MM (1998) J Natl Cancer Inst 90(9): 642-4
    › Primary publication · 9586655 (PubMed)
  28. Guidelines for the diagnosis of leukemia or lymphoma in children. Zutter MM, Hess JL (1998) Am J Clin Pathol 109(4 Suppl 1): S9-22
    › Primary publication · 9533745 (PubMed)
  29. Bone marrow staging in patients with non-Hodgkin's lymphoma: is flow cytometry a useful test? Naughton MJ, Hess JL, Zutter MM, Bartlett NL (1998) Cancer 82(6): 1154-9
    › Primary publication · 9506363 (PubMed)
  30. The ups and downs of alpha 2 beta 1-integrin expression: contributions to epithelial cell differentiation and the malignant phenotype. Zutter MM, Santoro SA (1998) Curr Top Microbiol Immunol : 167-85
    › Primary publication · 9479866 (PubMed)
  31. A three-dimensional collagen lattice activates NF-kappaB in human fibroblasts: role in integrin alpha2 gene expression and tissue remodeling. Xu J, Zutter MM, Santoro SA, Clark RA (1998) J Cell Biol 140(3): 709-19
    › Primary publication · 9456329 (PubMed) · PMC2140166 (PubMed Central)
  32. NAG-2, a novel transmembrane-4 superfamily (TM4SF) protein that complexes with integrins and other TM4SF proteins. Tachibana I, Bodorova J, Berditchevski F, Zutter MM, Hemler ME (1997) J Biol Chem 272(46): 29181-9
    › Primary publication · 9360996 (PubMed)
  33. Binding of phosphorylated Sp1 protein to tandem Sp1 binding sites regulates alpha2 integrin gene core promoter activity. Zutter MM, Ryan EE, Painter AD (1997) Blood 90(2): 678-89
    › Primary publication · 9226168 (PubMed)
  34. PDGF induction of alpha 2 integrin gene expression is mediated by protein kinase C-zeta. Xu J, Zutter MM, Santoro SA, Clark RA (1996) J Cell Biol 134(5): 1301-11
    › Primary publication · 8794869 (PubMed) · PMC2120983 (PubMed Central)
  35. Characterization of novel complexes on the cell surface between integrins and proteins with 4 transmembrane domains (TM4 proteins). Berditchevski F, Zutter MM, Hemler ME (1996) Mol Biol Cell 7(2): 193-207
    › Primary publication · 8688552 (PubMed) · PMC275873 (PubMed Central)
  36. Immunophenotypic analysis of hematologic malignancy by laser scanning cytometry. Clatch RJ, Walloch JL, Zutter MM, Kamentsky LA (1996) Am J Clin Pathol 105(6): 744-55
    › Primary publication · 8659450 (PubMed)
  37. Juvenile chronic myelogenous leukemia. Hess JL, Zutter MM, Castleberry RP, Emanuel PD (1996) Am J Clin Pathol 105(2): 238-48
    › Primary publication · 8607451 (PubMed)
  38. The alpha 2 beta 1 integrin: a collagen receptor on platelets and other cells. Santoro SA, Zutter MM (1995) Thromb Haemost 74(3): 813-21
    › Primary publication · 8571303 (PubMed)
  39. Recurrent neuroendocrine (Merkel cell) carcinoma of the skin presenting as marrow failure in a man with systemic lupus erythematosus. Lentz SR, Krewson L, Zutter MM (1993) Med Pediatr Oncol 21(2): 137-41
    › Primary publication · 8433681 (PubMed)
  40. Altered integrin expression in adenocarcinoma of the breast. Analysis by in situ hybridization. Zutter MM, Krigman HR, Santoro SA (1993) Am J Pathol 142(5): 1439-48
    › Primary publication · 8388172 (PubMed) · PMC1886906 (PubMed Central)
  41. Megakaryoblastic leukemia presenting as a temporal bone granulocytic sarcoma. Case report. Kaufman BA, Jones L, Zutter MM, Park TS (1993) J Neurosurg 79(1): 128-31
    › Primary publication · 8315452 (PubMed)
  42. The human alpha 2 integrin gene promoter. Identification of positive and negative regulatory elements important for cell-type and developmentally restricted gene expression. Zutter MM, Santoro SA, Painter AS, Tsung YL, Gafford A (1994) J Biol Chem 269(1): 463-9
    › Primary publication · 8276836 (PubMed)
  43. Dysplastic haemopoiesis following orthotopic liver transplantation: comparison with similar changes in HIV infection and primary myelodysplasia. Clatch RJ, Krigman HR, Peters MG, Zutter MM (1994) Br J Haematol 88(4): 685-92
    › Primary publication · 7819094 (PubMed)
  44. Alteration of collagen-dependent adhesion, motility, and morphogenesis by the expression of antisense alpha 2 integrin mRNA in mammary cells. Keely PJ, Fong AM, Zutter MM, Santoro SA (1995) J Cell Sci : 595-607
    › Primary publication · 7769004 (PubMed)
  45. Analysis of collagen receptors. Santoro SA, Zutter MM, Wu JE, Staatz WD, Saelman EU, Keely PJ (1994) Methods Enzymol : 147-83
    › Primary publication · 7760733 (PubMed)
  46. Re-expression of the alpha 2 beta 1 integrin abrogates the malignant phenotype of breast carcinoma cells. Zutter MM, Santoro SA, Staatz WD, Tsung YL (1995) Proc Natl Acad Sci U S A 92(16): 7411-5
    › Primary publication · 7638207 (PubMed) · PMC41349 (PubMed Central)
  47. Regulation of alpha 2 integrin gene expression in cells with megakaryocytic features: a common theme of three necessary elements. Zutter MM, Painter AA, Staatz WD, Tsung YL (1995) Blood 86(8): 3006-14
    › Primary publication · 7579393 (PubMed)
  48. Epstein-Barr virus lymphoproliferation after bone marrow transplantation. Zutter MM, Martin PJ, Sale GE, Shulman HM, Fisher L, Thomas ED, Durnam DM (1988) Blood 72(2): 520-9
    › Primary publication · 2840986 (PubMed)
  49. Necrotizing granulomatosis of the spleen in chronic granulomatous disease. Atlas AB, Manthei U, Zutter MM, Polmar SH (1990) Am J Dis Child 144(1): 14-5
    › Primary publication · 2403745 (PubMed)
  50. Acute lymphoblastic leukemia. An unusual case of primary relapse in the uterine cervix. Zutter MM, Gersell DJ (1990) Cancer 66(5): 1002-4
    › Primary publication · 2386910 (PubMed)
  51. Decreased expression of integrin adhesive protein receptors in adenocarcinoma of the breast. Zutter MM, Mazoujian G, Santoro SA (1990) Am J Pathol 137(4): 863-70
    › Primary publication · 2221016 (PubMed) · PMC1877561 (PubMed Central)
  52. Secondary T-cell lymphoproliferation after marrow transplantation. Zutter MM, Durnam DM, Hackman RC, Loughran TP, Kidd PG, Ashley RL, Petersdorf EW, Martin PJ, Thomas ED (1990) Am J Clin Pathol 94(6): 714-21
    › Primary publication · 2173884 (PubMed)
  53. Widespread histologic distribution of the alpha 2 beta 1 integrin cell-surface collagen receptor. Zutter MM, Santoro SA (1990) Am J Pathol 137(1): 113-20
    › Primary publication · 2164774 (PubMed) · PMC1877693 (PubMed Central)
  54. Immunolocalization of integrin receptors in normal lymphoid tissues. Zutter MM (1991) Blood 77(10): 2231-6
    › Primary publication · 2029582 (PubMed)
  55. Identification of a tetrapeptide recognition sequence for the alpha 2 beta 1 integrin in collagen. Staatz WD, Fok KF, Zutter MM, Adams SP, Rodriguez BA, Santoro SA (1991) J Biol Chem 266(12): 7363-7
    › Primary publication · 2019571 (PubMed)
  56. Expression of Epstein-Barr virus-encoded growth-transformation-associated proteins in lymphoproliferations of bone-marrow transplant recipients. Gratama JW, Zutter MM, Minarovits J, Oosterveer MA, Thomas ED, Klein G, Ernberg I (1991) Int J Cancer 47(2): 188-92
    › Primary publication · 1846349 (PubMed)
  57. Collagen-induced release of interleukin 1 from human blood mononuclear cells. Potentiation by fibronectin binding to the alpha 5 beta 1 integrin. Pacifici R, Basilico C, Roman J, Zutter MM, Santoro SA, McCracken R (1992) J Clin Invest 89(1): 61-7
    › Primary publication · 1729281 (PubMed) · PMC442819 (PubMed Central)
  58. CD7+ acute non-lymphocytic leukemia: evidence for an early multipotential progenitor. Zutter MM, Martin PJ, Hanke D, Kidd PG (1990) Leuk Res 14(1): 23-6
    › Primary publication · 1689436 (PubMed)
  59. Induced cell surface expression of functional alpha 2 beta 1 integrin during megakaryocytic differentiation of K562 leukemic cells. Burger SR, Zutter MM, Sturgill-Koszycki S, Santoro SA (1992) Exp Cell Res 202(1): 28-35
    › Primary publication · 1511736 (PubMed)
  60. Differential regulation of the alpha 2 beta 1 and alpha IIb beta 3 integrin genes during megakaryocytic differentiation of pluripotential K562 cells. Zutter MM, Fong AM, Krigman HR, Santoro SA (1992) J Biol Chem 267(28): 20233-8
    › Primary publication · 1400341 (PubMed)