Pharmacological Sciences

Associate Professor, Pharmacological Sciences
Ph.D.: University of Texas Southwestern Medical Center at Dallas
Postdoctoral: Vanderbilt University
e-mail: crawford@pharm.stonybrook.edu
Selected Publications
4-3085

Pancreatic cancer is the 5^th most common cause of cancer related death in the United States. With about 30,000 Americans being diagnosed with pancreatic cancer each year, the disease incidence is relatively low compared to other cancers. However, with only a 4% 5-year survival rate, the prognosis for someone with pancreatic cancer is dismal. There are two major reasons for the difficulty in dealing with pancreatic cancer. First, it generally remains asymptomatic until the cancer has progressed to a very late stage. Second, pancreatic cancer is resistant to most current cancer therapies.

In my laboratory, we study matrix metalloproteinase-7 (MMP-7), a secreted proteolytic enzyme that is expressed in a very high proportion of pancreatic tumors. Using MMP-7 as window into pancreatic cancer, we are identifying the signal transduction pathways that are active in the diseased pancreas and using what we find to develop animal models that accurately reflect the human disease. We are also testing the function of MMP-7 in existing animal models of pancreatic cancer to determine if the use of MMP-7 inhibitors holds promise in both prevention and treatment of early stage pancreatic cancer. Finally, because MMP-7 is a secreted protein, we are testing whether screening for MMP-7 will be a useful non-invasive diagnostic tool for detecting early stage pancreatic cancer.

Selected Publications:

H.C. Crawford and L.M. Matrisian. Tumor and stromal expression of matrix metalloproteinases and their role in tumor progression. (1994). Invasion and Metastasis 14: 234-245.

H.C. Crawford and L.M. Matrisian. Mechanisms controlling the transcription of matrix metalloproteinase genes in normal and neoplastic cells. (1996). Enzyme and Protein 49: 20-37.

J. Dong, H.C. Crawford, V. Lavrovsky, D. Taub, R. Watts, L.M. Matrisian, and N.H. Colburn. A dominant negative mutant of jun blocking 12-O-Tetradecanoylphorbol-13-acetate-induced invasion in mouse keratinocytes. (1997). Mol. Carcinogen. 19:204-212.

H.C. Crawford, L.M. Matrisian, and L. Liaw. Distinct roles of osteopontin in host defense activity and tumor survival during squamous cell carcinoma progression in vivo. (1998). Cancer Res., 58, 5206-5215.

H.C. Crawford, B. Fingleton, L. Rudolph-Owen, K. Heppner Goss, B. Rubinfeld, P. Polakis and L.M. Matrisian. The metalloproteinase matrilysin is a target of b-catenin transactivation. (1999). Oncogene, 18, 2883-2891.

B.M. Fingleton, K.J. Heppner Goss, H.C. Crawford and L.M. Matrisian. Matrilysin in early stage intestinal tumorigenesis. (1999). APMIS 107, 102-110.

H. Haro, H.C. Crawford, B. Fingleton, K. Shinomiya, D.M. Spengler and L.M. Matrisian. Matrix metalloproteinase-7-dependent release of tumor necrosis factor-alpha in a model of herniated disc resorption. (2000). J.Clin. Invest. 105:143-50.

H. Haro, H.C. Crawford, B. Fingleton, J.R. MacDougall, K. Shinomiya, D.M. Spengler and L.M. Matrisian. Matrix metalloproteinase-3-dependent generation of a macrophage chemoattractant in a model of herniated disc resorption. (2000) J. Clin. Invest. 105:133-41.

R. Fenrick, L. Wang, J. Nip, J. M. Amann, R. J. Rooney, J. Walker-Daniels, H.C. Crawford, D. L. Hulboy, M. S. Kinch, L. M. Matrisian, and S. W. Hiebert. TEL, a putative tumor suppressor, modulates cell growth and cell morphology of Ras-transformed cells while repressing the transcription of stromelysin-1. (2000) Mol. Cell. Biol. 20: 5828-5839.

P.Z. Anastasiadis, S.Y. Moon, M.A. Thoreson, D.J. Mariner, H.C. Crawford, Y.Zheng, and A.B. Reynolds. Inhibition of RhoA by p120 catenin. (2000) Nat. Cell Biol., 2: 637-644.

V. Noe, B. Fingleton, K. Jacobs, H.C. Crawford, S. Vermeulen, E. Bruyneel, L.M. Matrisian and M. Mareel. Release of an invasion promoter E-cadherin fragment by matrilysin and stromelysin-1. (2001) J.Cell Sci. 114: 111-118.

H.C. Crawford, B. Fingleton, M.D.Gustavson, R.A.Wagenaar, J.A.Hassell and L.M.Matrisian. The PEA3 subfamily of Ets proteins synergizes with b-catenin/LEF to upregulate matrilysin expression in intestinal tumors. (2001) Mol. Cell. Biol, 21 (4): 1370-1383.

R.A. Wagenaar, H.C. Crawford, and L.M. Matrisian. Stabilized b-catenin immortalizes colonic epithelial cells. (2001) Cancer Res. 61: 2097-2104

L.R. Howe, H.C. Crawford, J.A. Hassell, A.J. Dannenberg and A.M.C. Brown. PEA3 is upregulated in response to WNT-1 and regulates the expression of cyclooxygenase-2. (2001) J. Biol. Chem. 276: 20108-20115.

D.L. Hulboy, L.M. Matrisian and H.C. Crawford. Downregulation of JunB activity contributes to stromelysin-1 expression in the epithelial to mesenchymal transition of mouse skin tumors. (2001). Mol. Cell. Biol. 21: 5478-5487.

R Agninotri, H.C. Crawford, H. Haro, L.M.Matrisian, M.C. Havrada and L. Liaw. Osteopontin, a novel substrate for matrix metalloproteinase-3 (stromelysin-1) and matrix metalloproteinase-7 (matrilysin). (2001). J. Biol. Chem. 276: 28261-28267.

B. Fingleton, T. Vargo, H.C. Crawford and L.M. Matrisian. Matrilysin expression selects for cells with reduced sensitivity to Fas-mediated apoptosis. (2001). Neoplasia 3: 459-468.

H.C. Crawford, C.R. Scoggins, M.K. Washington, L.M. Matrisian and S.D. Leach. Matrix metalloproteinase-7 is expressed in pancreatic cancer precursors and regulates acinar-to-ductal cell metaplasia in the exocrine pancreas. (2002) J.Clin.Invest. 109: 1437-1444.

J.M. Daniel , C.M. Spring, H.C. Crawford, A.B. Reynolds and A. Baig. The p120^CTN-binding partner Kaiso is a bi-modal DNA-finding protein that recognizes both sequence-specific consensus and methylated CpG dinucleotides. (2002) Nuc. Acids Res. 30: 2911-2919.

T.G. Vargo-Gogola, B. Fingleton, H.C. Crawford and L.M. Matrisian. Matrilysin (MMP-7) selects for apoptosis-resistant mammary cells in vivo. (2002) Cancer Res. 65: 5559-5563.

T.G. Vargo-Gogola, H.C. Crawford and L.M. Matrisian. Identification of novel matrix metalloproteinase-7 (matrilysin) cleavage sites in murine and human Fas ligand. (2002). Arch Biochem Biophys 408:155-161.

C. Rivat, N. Le Floch, M. Sabbah, G. Redeuilh, E. Bruyneel, M. Mareel, L.M. Matrisian, H.C. Crawford, C. Gespach and S. Attoub. Synergistic cooperation between the AP-1 and LEF-1 transcription factors in the activation of the matrilysin promoter by the src oncogene: implications for cellular invasion. In press.

Y. Liu, H. Jiang, H.C. Crawford and B.L.M.Hogan. Molecular phenotyping of the distal tip endoderm of the embryonic mouse lung. In press.

H.C. Crawford, U.S. Krishna, D.A. Israel and R. Peek. Helicobacter pylori cag⁺ strains selectively induce MMP-7 in vitro and within inflamed gastric mucosa. Submitted.

H.C. Crawford and L.M. Matrisian. Stromelysin-1 is protective against skin tumor growth and progression. Submitted.