Scripps Research Logo

Molecular Medicine

Faculty

James P. Quigley, Ph.D.

Professor
Department of Molecular Medicine
California Campus
Laboratory Website
jquigley@scripps.edu
(858) 784-7108

Scripps Research Joint Appointments

Faculty, Graduate Program

Research Focus

Identification of Molecules and Pathways that Function in Human Tumor Metastasis and Angiogenesis for Possible Therapeutic Application

Our laboratory is conducting studies on the mechanism of human tumor metastasis using an in vivo model system that employs human tumor cells disseminating to specific organs in the developing chick embryo. This very rapid, fascile and quantitative in vivo model system is used as our initial molecular discovery-based model. When specific contributing molecules or pathways are identified in the chick system, distinct mouse metastasis models are employed to affirm these discoveries and identifications. The ongoing mouse models include both orthotopic tissue implantations and i.v. inoculations of tumor cells directly into the circulation.

A technique known as subtractive immunization is employed to generate in an unbiased manner unique antibodies directed against antigens on the surface of metastatic human tumor cells which are then tested for their ability to modulate metastatic spread in the various live animal models. Tumor cell surface antigens that are functionally involved in metastasis are being identified by these methods. The quantitation of metastasis, using real time qPCR with human specific primers, has allowed for the in vivo selection and isolation of unique tumor cell variant pairs from human fibrosarcomas and prostate, epidermoid and pancreatic carcinomas that greatly differ in their metastatic capabilities. Comparative analyses of the gene and protein expression levels of the human tumor variants are providing distinct information about metastasis-specific molecules.

Also under way in the laboratory is an investigation of a specific early step in metastasis, namely, the process of intravasation, which is the entry of primary tumor cells into the vasculature and is likely a rate-limiting step in tumor dissemination. Three pairs of isogenic human tumor variants have now been isolated and shown to have a 25-100 fold differential in their respective ability to enter the vasculature and disseminate in vivo. The cellular and molecular analysis of these variants using array technology, proteomic approaches, and intravital microscopy has allowed us to identify specific contributory molecules that are functionally important in tumor cell/vascular interactions and impact the intravasation step in the metastatic cascade.

Our laboratory is also examining the differential expression of specific proteolytic enzymes and how these enzymes may mediate angiogenesis and tumor cell migration and invasion. The experimental approach is to employ chemical-based assays to detect those enzymes which are distinctly activated in angiogenic tissue, or around invading tumor cells. We then generate specific mutant constructs, inhibitors or neutralizing antibodies to the enzymes, all of which are then tested in various in vivo model systems that manifest the angiogenic or invasive phenotype. This approach allows for the identification of specific proteolytic enzymes that are functionally involved in distinct physiological and pathological processes. Two enzyme families presently under study include the matrix metallo proteases (e.g. MMP-9, MMP-1) and the serine proteases, (e.g. uPA and plasmin). New cell surface substrates for these proteases have recently been identified and their cleavage has been shown to activate important signaling cascades.

We also have ongoing studies in the lab examining the role of inflammatory neutrophils that influx into developing primary tumors. The influx of these “first responder” cells appears to be driven by the inappropriate overexpression by tumor cells of specific cytokines that attract various types of inflammatory cells. We are presently focusing on neutrophil influx since these cells deliver to the developing tumor tissue a distinct proteolytic enzyme (TIMP-free MMP-9) that is a potent angiogenic agent. The biochemical mechanisms behind the angiogenesis-inducing capabilities of this enzyme are currently being investigated.

Education

Ph.D., Biology, Johns Hopkins University, 1970

Selected References

Complete List of Published Work in My Bibliography

Zijlstra A, Lewis J, DeGryse B, Stuhlman H and Quigley JP. The inhibition of tumor cell intravasation and subsequent metastasis through the regulation of in vivo tumor cell motility by the tetraspanin CD151. Cancer Cell 2008;13(3):221-34.

Deryugina EI, Conn EM, Wortmann A, Partridge, JJ, Kupriyanova TA, Ardi VC, Hooper JD and Quigley JP. . Functional Role of Cell Surface CUB Domain-Containing Protein 1 (CDCP1) in Tumor Cell Dissemination. Mol Cancer Res. 2009;7(8):1197-211.

Conn EM, Botkjaer KA, Kupriyanova TA, Andreasen PA, Deryugina EI, Quigley JP.. Comparative analysis of metastasis variants derived from human prostate carcinoma cells: roles in intravasation of VEGF-mediated angiogenesis and uPA-mediated invasion. Am J Pathol. 2009;175(4):1638-52. http://ajp.amjpathol.org/cgi/reprint/175/4/1638.

Ardi VC, Van den Steen PE, Opdenakker G, Schweighofer B, Deryugina EI and Quigley JP. Neutrophil proMMP-9, unencumbered by TIMP-1, undergoes efficient activation in vivo and catalytically induces angiogenesis via an FGF-2/FGFR2 pathway. J Biol Chem. 2009;38:25854-66.

Botkjaer KA, Fogh S, Bekes EC, Chen Z, Blouse GE, Jensen JM, Mortensen KK, Huang M, Deryugina E, Quigley JP, Declerck PJ, Andreasen PA.  Targeting the autolysis loop of urokinase-type plasminogen activator with conformation-specific monoclonal antibodies.  Biochem J. 2011 Aug 15;438(1):39-51.  PMID: 21635223

Bekes EM, Schweighofer B, Kupriyanova TA, Ardi VC, Zajac E, Quigley JP, Deryugina EI.  Tumor-recruited neutrophils and neutrophil TIMP-free MMP-9 regulate coordinately the levels of tumor angiogenesis and efficiency of malignant cell intravasation. Am J Pathol. 2011 Sep; 179(3):1455-70.  PMCID: PMC3157227

Bekes EM, Deryugina EI, Kuprianova TA, Zajac E, Botkjaer KA, Andreasen PA, Quigley JP. Activation of pro-uPA is critical for initial escape from the primary tumor and hematogenous dissemination of human carcinoma cells.  Neoplasia. 2011 Sep; 13(9):806-21.  PMCID: PMC3182273

Quigley JP and Deryugina EI. Combating angiogenesis early: potential of targeting tumor-recruited neutrophils in cancer therapy.  Future Oncol. 2012 Jan;8(1):5-8.  PMID: 22149028

Casar B, He Y, Iconomou M, Hooper JD, Quigley JP, Deryugina EI. Blocking of CDCP1 cleavage in vivo prevents Akt-dependent survival and inhibits metastatic colonization through PARP1-mediated apoptosis of cancer cells. Oncogene. 2012 Aug 30;31(35):3924-38. PMCID: PMC4350937

Botkjaer KA, Deryugina EI, Dupont DM, Bekes EM, Gardsvoll H, Thuesen CK, Chen Z, Ploug M, Quigley JP, Andreasen PA. Targeting tumor cell invasion and dissemination in vivo by an aptamer that inhibits urokinase-type plasminogen activator through a novel multi-functional mechanism. Mol Cancer Res. 2012 10(12):1532-43.  PMCID: PMC3528818

Kato H, Liao Z, Mitsios JV, Wang HY, Deryugina EI, Varner JA, Quigley JP, Shattil SJ. The primacy of ß1 integrin activation in the metastatic cascade. PLoS One. 2012;7(10):e46576.  PMCID: PMC3463578

Deryugina EI and Quigley JP. Review Article: Cell surface remodeling by plasmin: a new function for an old enzyme. Hindawi Publishing Corporation Journal of Biomedicine and Biotechnology. Volume 2012, Article ID 564259, 21 pages. PMCID: PMC3477900

Low-Marchelli JM, Ardi VC, Vizcarra EA, van Rooijen N, Quigley JP, Yang J. Twist1 induces CCL2 and recruits macrophages to promote angiogenesis. Cancer Research.  2013;73(2):622-71.  PMCID: 3566985

Juncker-Jensen A, Deryugina EI, Rimann I, Zajac E, Kupriyanova TA, Engelholm LJ, Quigley JP. Tumor MMP-1 activates endothelial PAR1 to facilitate vascular intravasation and metastatic dissemination. Cancer Res. 2013 Jul 15;73(14):4196-211. PMID: 23687338

Zajac E, Schweighofer B, Kupriyanova TA, Juncker-Jensen A, Minder P, Quigley JP, Deryugina EI. Angiogenic capacity of M1- and M2-polarized macrophages is determined by the levels of TIMP-1 complexed with their secreted proMMP-9. Blood. 2013 Dec 12;122(25):4054-67. PMCID: PMC3862278

Casar B, Rimann I, Kato H, Shattil SJ, Quigley J, Deryugina EI. In vivo cleaved CDCP1 promotes early tumor dissemination via complexing with activated ß1 integrin and induction of FAK/PI3K/Akt motility signaling. Oncogene. 2014 Jan 9;33(2)255-68.  PMCID: PMC3931462

Deryugina EI, Zajac E, Juncker-Jensen A, Kupriyanova TA, Welter L, Quigley JP. Tissue-infiltrating neutrophils constitute the major in vivo source of angiogenesis-inducing MMP-9 in the tumor microenvironment. Neoplasia. 2014 Oct 23;16(10):771-88. PMCID: PMC4212255

Vandooren J, Born B, Solomonov I, Zajac E, Saldova R, Senske M, Ugarte-Berzal E, Martens E, Van den Steen PE, Van Damme J, Garcia-Pardo A, Froeyen M, Deryugina EI, Quigley JP, Moestrup SK, Rudd PM, Sagi I, Opdenakker G. Circular trimers of gelatinase B/matrix metalloproteinase-9 constitute a distinct population of functional enzyme molecules differentially regulated by tissue inhibitor of metalloporoteinases-1. Biochem J. 2015 Jan 15;465(2):259-70. PMCID: PMC4399976

Deryugina EI, Quigley JP. Tumor angiogenesis: MMP-mediated induction of intravasation- and metastasis-sustaining nevasculature. Matrix Biol. 2015 May-Jul;44-46:94-112. Review. PMID: 25912949

Minder P, Zajac E, Quigley JP, Deryugina EI. EGFR regulates the development and microarchitecture of intratumoral angiogenic vasculature capable of sustaining cancer cell intravasation. Neoplasia. 2015 Aug;17(8):634-49. PMID: 26408256

Links

Team Wins $1.8 Million to Study Early Events in Cancer Metastasis

TSRI Study Suggests Tumors May ‘Seed’ Cancer Metastases Earlier Than Expected

Scripps Research Scientists Illuminate Cancer Cells’ Survival Strategy During Dangerous Dissemination

Team Reveals How White Blood Cell Promotes Growth and Spread of Cancer

Quigley Lab Website

Molecular Medicine Seminar Series

CA Faculty

Asahara, Hiroshi
Balch, William E.
Boddy, Michael
Buxbaum, Joel
Catz, Sergio
Conti, Bruno
Cravatt, Benjamin
D'Lima, Darryl
DerMardirossian, Celine
Deryugina, Elena
Elias, Darlene
Encalada, Sandra
Felding, Brunhilde
Fowler, Velia
Friedlander, Martin
Gerace, Larry
Gottesfeld, Joel
Griffin, John
Hanneken, Anne
Heeb, Mary Jo
Henderson, Scott
Hoch, James
Joazeiro, Claudio
Johnson, Eric
Kanaji, Taisuke
Kay, Steve
Kelly, Jeffery
Koziol, James
Lamia, Katja
Lazzerini Denchi, Eros
Lipton, Stuart
Loring, Jeanne F.
Loskutoff, David
Lotz, Martin
Makarenkova, Helen P.
Mc Millan, Robert
Miles, Lindsey
Milner, Richard
Modena, Brian
Mosnier, Laurent
Paulson, James C.
Perego, Marta
Petrascheck, Michael
Pollard, Kenneth Michael
Quigley, James P.
Reed, Steven
Roberts, Edward
Rosen, Hugh
Ruggeri, Zaverio
Russell, Paul
Saez, Enrique
Smider, Vaughn
Srinivasan, Supriya
Steinhubl, Steven
Sutcliffe, J.
Tan, Eng
Topol, Eric
Vanderklish, Peter
Vogt, Peter K.
Waalen, Jill
Wiseman, Luke
Wittenberg, Curt
Wolan, Dennis W.
Wu, Peng
Wu, Xiaohua
Yang, Xiang-Lei
Yates III, John


FL Faculty

Bohn, Laura M.
Cameron, Michael
Duckett, Derek
Gill, Matt
Griffin, Patrick
Hansen, Scott
Kamenecka, Theodore
Kissil, Joseph
Luo, Junli
McDonald, Patricia
Miller, Courtney
Niedernhofer, Laura
Phinney, Donald G.
Robbins, Paul
Scampavia, Louis
Schimmel, Paul
Smith, Roy
Spicer, Timothy


Affiliated Faculty

Cline, Hollis
Kojetin, Douglas
Lairson, Luke
Paegel, Brian
Rumbaugh, Gavin
Shen, Ben
Solt, Laura A
Su, Andrew
Wu, Chunlei


Adjunct Faculty