Tumor Cell Metastasis
Trevor K. Archer, Ph.D.
Principal Investigator and Chief,
Laboratory of Molecular Carcinogenesis
John D. Roberts, Ph.D.
Tel (919) 541-5023
Fax (919) 541-0076
email@example.com P.O. Box 12233
Mail Drop D2-05
Research Triangle Park, North Carolina 27709
The metastatic spread of cancer cells is the primary cause of morbidity and mortality in cancer patients. The aims of the Metastasis Group are to understand the mechanisms by which tumor cells metastasize and to define the signaling pathways that regulate this process, with an emphasis on defining environmental factors and potential antimetastatic agents that may modulate these pathways. The group has demonstrated that omega-6 cis-polyunsaturated fatty acids, such as arachidonic acid, stimulate adhesion of human tumor cells to type IV collagen through a pathway that involves mitogen activated protein (MAP) kinases, protein kinase C, protein kinase D, and β1 integrins. p38 MAP kinase, a key signal transduction protein, is activated during this process and is critical for the adhesion of these cells to an extracellular matrix. Studies have defined both upstream and downstream components of the p38 pathway, demonstrating that p38 is activated through TAK1 and MKK6 and that p38 both activates MAPKAPK2 and associates with the focal adhesion protein vinculin during cell adhesion. Members of the laboratory are pursuing the potential role of this association in the regulation of critical cytoskeletal rearrangements that lead to increased cell adhesion and motility.
In an apparently independent pathway, protein kinase C epsilon and PKD1 (formerly called PKC mu) are activated in tumor cells in response to arachidonic acid. The Metastasis group has discovered a novel role for the neutral Ca+ dependent protease, calpain, in processing the PKD1 to a more active kinase in fatty acid treated cells. Molecular constructs and proteomic techniques are being used to identify targets of processed PKD that are critical for tumor cell adhesion and invasion.
The Metastasis Group has shown that products of arachidonic acid metabolism by 15-lipoxygenase-2 are the most likely candidates for activation of the adhesion process. Current research is focused on determining the point at which fatty acid metabolites activate the kinase pathways in these cells and how this might be inhibited. In addition, the Metastasis Group has examined the role of small GTPases in the regulation of adhesion in human tumor cells exposed to dietary fatty acids and found that arachidonic acid induces a decrease in Rac and an increase in RhoA activity. Blocking Rho and its effector ROCK inhibited this adhesion. Moreover, proteins that co-precipitated with Rho-GTP were identified by mass spectrometry. One of the proteins identified in a complex with Rho-GTP was nucleolin. Arachidonic acid induces serine phosphorylation of this nucleolar protein and this phosphorylation is dependent on ROCK activity. shRNA knockdown of nucleolin blocked the fatty acid-induced cell adhesion, suggesting that nucleolin functions as a novel down stream effector for RhoA and ROCK.
The Metastasis Group is now extending this work to a nude mouse model in which several human tumor cell lines are being tested for their ability to metastasize in animals fed diets differing in their fatty acid content. The laboratory plans to use this model to examine the changes in both tumor cell and host organ gene expression to understand the mechanisms by which receptive niches are established to which these tumor cells can metastasize, as well as to test strategies for inhibiting the metastatic process in vivo.
Major areas of research:
Trevor A. Archer, Ph.D., is Chief of the Laboratory of Molecular Carcinogenesis, but also leads the Chromatin & Gene Expression Group and the Metastasis Group. He earned his Ph.D. in 1987 at Queen’s University, Kingston, Ontario, Canada. He has published more than 60 peer-reviewed articles in leading biomedical journals as well as several book chapters. He served as a Tenured Associate Professor in the Departments of Biochemistry and Obstetrics and Gynecology at the University of Western Ontario in London, Canada before joining NIEHS in 1999.
John D. Roberts, Ph.D., is a staff scientist in the Metastasis Group and is responsible for its day-to-day operations. He earned his B.S. in chemistry from the University of North Carolina in 1976 and his Ph.D. in molecular biology in 1981 from Washington University, St. Louis. He was a postdoctoral fellow in the Biochemistry Department at the Johns Hopkins University School of Hygiene and Public Health, Baltimore, Maryland, prior to moving to the NIEHS. He has published over 30 peer-reviewed articles as well as several book chapters. He is also currently the Deputy Chair of the Institute’s Animal Care and Use Committee.