Phone: (615) 322-3295
Tumor cell invasion and cancer metastasis
Cancer Metastasis is initiated by the initial dissemination of tumor cells away from the primary tumor. We hypothesize that immobilization of tumor cells through enhanced adhesion can prevent systemic dissemination of tumor cells. A combination of in vivo models, biochemical assays and genetic screens is used to identify and alter the molecular components that can immobilize the metastasizing tumor cell.
Our research is based on two core technologies: We use the quantitative PCR mediated detection of human specific DNA repeat sequences to quantitatively assess metastasis in our in vivo models. In addition we utilize high-resolution, in vivo visualization of human tumor cell behavior in the avian embryo model using a novel intravital system of our own design. The laboratory’s primary focus is on tumor cell motility and molecular mechanisms of motility that facilitate local invasion and intravasation. However, the comprehensive nature of our in vivo systems allow for a complete analysis of the metastatic cascade from primary tumor growth and angiogenesis to arrest and organ colonization.
Among the molecular regulators of motility, we have found the tetraspanin CD151 to be a particularly critical component of metastasis. Interfering with its function through antibody binding inhibits extracellular matrix mediated migration and blocks >95% of the tumor cell dissemination in a spontaneous metastasis model. Using a newly-established in vivo motility assay, I have been able to demonstrate that altering the function of CD151 results in complete inhibition of in vivo motility for several tumor cell types. Furthermore, by implementing the quantitative PCR described above we have been able to determine that CD151 is critical for successful intravasation at the site of the primary tumor.
The laboratory pursues three primary research objectives: 1) Characterization of the molecular mechanism of migration regulated by the tetraspanin CD151, 2) Identification and characterization of the metastatic cell population within a primary tumor, and 3) In vivo screening for molecular mechanism of migration capable of reverting the invasive phenotype of metastatic tumor cells.
A. Zijlstra. (2009) Tetraspanins in Cancer. In: Cell-Extracellular Matrix Interactions in Cancer. Ed. Zent, R and Pozzi, A. Springer Science and Business Media.
Yi Zhang, Wendy Schulte, Desmond Pink, Andries Zijlstra, John Lewis, and David Morton Waisman (2010) Sensitivity of Cancer Cells to Truncated Diphtheria Toxin. PLOS ONE,5(5):e10498. (PMID: 20463924)
Choi-Fong Cho, Amber Ablack, Hon-Sing Leong, Andries Zijlstra, and John Lewis. (2011) Evaluation of nanoparticle uptake in tumors in real time using intravital imaging. JOVE (In Press)
Trenis D. Palmer, John D. Lewis, and Andries Zijlstra. (2011) Quantitative analysis of cancer metastasis using an avian embryo model. JOVE (In Press)
William Ashby and Andries Zijlstra. (2011) Beyond the Scratch Assay: Strategies for analyzing migration in vitro. Experimental Biology and Medicine (In Press)
Hon Sing Leong, Nicole F. Steinmetz, Amber Ablack, Giuseppe Destito, Andries Zijlstra, Heidi Stuhlmann, Marianne Manchester, John D. Lewis (2010) Viral nanoparticles as a platform for intravital imaging of embryonic and tumor neovasculature. Nature Protocols, 5, 1406–1417 (PMID: 20671724)
Andries Zijlstra. (2009) Launching an Academic Research Career. Dis Model Mech. 2009 Nov-Dec;2(11-12):526-30. (PMID: 19892881)
Norma E. Ramirez, Zhonghua Zhang, Aasakiran Madamanchi, Kelli L. Boyd, Lynda D. O’Rear, Abudi Nashabi, Zhengzi Li, William D. Dupont, Andries Zijlstra, and Mary M. Zutter. (2010) The α2β1 integrin is a metastasis suppressor in mouse models and human cancer. Journal of Clinical Investigations doi:10.1172/JCI42328 (PMID: 21135504)
Trenis Palmer and Andries Zijlstra. (2011) CD151. Molecular Pages in Nature Signaling. In Press
Trenis D. Palmer, William Ashby, John D. Lewis, and Andries Zijlstra. (2011) Targeting Tumor Cell Motility and Metastasis. Advanced Drug Delivery Reviews (In Press)
Amanda Hansen and Andries Zijlstra. (2011) ALCAM. Molecular Pages in Nature Signaling. (InPress)
Andries Zijlstra. Tetraspanins in Cancer. In: Cell-Extracellular Matrix Interactions in Cancer, Springer Science + Business Media(1st Ed.), 217-244, 2010.
Zijlstra, A. Launching an academic research career. Dis Model Mech, 2(11-12), 526-30, 2009.
Zijlstra, A, Lewis, J, Degryse, B, Stuhlmann, H, Quigley, JP. The inhibition of tumor cell intravasation and subsequent metastasis via regulation of in vivo tumor cell motility by the tetraspanin CD151. Cancer Cell, 13(3), 221-34, 2008.
FÃ©ral, CC, Zijlstra, A, Tkachenko, E, Prager, G, Gardel, ML, Slepak, M, Ginsberg, MH. CD98hc (SLC3A2) participates in fibronectin matrix assembly by mediating integrin signaling. J Cell Biol, 178(4), 701-11, 2007. PMCID:2064475
Lewis, JD, Destito, G, Zijlstra, A, Gonzalez, MJ, Quigley, JP, Manchester, M, Stuhlmann, H. Viral nanoparticles as tools for intravital vascular imaging. Nat Med, 12(3), 354-60, 2006. PMCID:2536493
Zijlstra, A, Quigley, JP. The DARC side of metastasis: shining a light on KAI1-mediated metastasis suppression in the vascular tunnel. Cancer Cell, 10(3), 177-8, 2006.
Zijlstra, A, Seandel, M, Kupriyanova, TA, Partridge, JJ, Madsen, MA, Hahn-Dantona, EA, Quigley, JP, Deryugina, EI. Proangiogenic role of neutrophil-like inflammatory heterophils during neovascularization induced by growth factors and human tumor cells. Blood, 107(1), 317-27, 2006. PMCID:1895349
Blancafort, P, Chen, EI, Gonzalez, B, Bergquist, S, Zijlstra, A, Guthy, D, Brachat, A, Brakenhoff, RH, Quigley, JP, Erdmann, D, Barbas, CF. Genetic reprogramming of tumor cells by zinc finger transcription factors. Proc Natl Acad Sci U S A, 102(33), 11716-21, 2005. PMCID:1187960
Deryugina, EI, Zijlstra, A, Partridge, JJ, Kupriyanova, TA, Madsen, MA, Papagiannakopoulos, T, Quigley, JP. Unexpected effect of matrix metalloproteinase down-regulation on vascular intravasation and metastasis of human fibrosarcoma cells selected in vivo for high rates of dissemination. Cancer Res, 65(23), 10959-69, 2005.
Wilson, S, Greer, B, Hooper, J, Zijlstra, A, Walker, B, Quigley, J, Hawthorne, S. The membrane-anchored serine protease, TMPRSS2, activates PAR-2 in prostate cancer cells. Biochem J, 388(Pt 3), 967-72, 2005. PMCID:1183478
Zijlstra, A, Aimes, RT, Zhu, D, Regazzoni, K, Kupriyanova, T, Seandel, M, Deryugina, EI, Quigley, JP. Collagenolysis-dependent angiogenesis mediated by matrix metalloproteinase-13 (collagenase-3). J Biol Chem, 279(26), 27633-45, 2004.
Aimes, RT, Zijlstra, A, Hooper, JD, Ogbourne, SM, Sit, ML, Fuchs, S, Gotley, DC, Quigley, JP, Antalis, TM. Endothelial cell serine proteases expressed during vascular morphogenesis and angiogenesis. Thromb Haemost, 89(3), 561-72, 2003.
Hooper, JD, Zijlstra, A, Aimes, RT, Liang, H, Claassen, GF, Tarin, D, Testa, JE, Quigley, JP. Subtractive immunization using highly metastatic human tumor cells identifies SIMA135/CDCP1, a 135 kDa cell surface phosphorylated glycoprotein antigen. Oncogene, 22(12), 1783-94, 2003.
Zijlstra, A, Testa, JE, Quigley, JP. Targeting the proteome/epitome, implementation of subtractive immunization. Biochem Biophys Res Commun, 303(3), 733-44, 2003.
Zijlstra, A, Mellor, R, Panzarella, G, Aimes, RT, Hooper, JD, Marchenko, ND, Quigley, JP. A quantitative analysis of rate-limiting steps in the metastatic cascade using human-specific real-time polymerase chain reaction. Cancer Res, 62(23), 7083-92, 2002.
Balza, E, Castellani, P, Zijlstra, A, Neri, D, Zardi, L, Siri, A. Lack of specificity of endoglin expression for tumor blood vessels. Int J Cancer, 94(4), 579-85, 2001.
Zijlstra, A, McCabe, NR, Schelling, ME. Expression and assembly of the angiogenic marker B-fibronectin by endothelial cells in vitro: regulation by confluency. Angiogenesis, 3(1), 77-87, 1999.
Zijlstra, A, Schelling, ME. Detection of multiple fibronectin isoforms in fetal fibroblast monolayer culture: a novel method for the qualitative and quantitative detection of multiple antigens. Histochem Cell Biol, 111(2), 163-9, 1999.