Department of Biochemistry

Steven Frisch, Ph.D.

B.S. - State University of New York , Stony Brook , NY, 1977
Ph.D. - University of California , Berkeley , CA, 1984
Postdoctoral - Center for Cancer Research, MIT, Cambridge , MA, 1985-87

Professor
Department of Biochemistry
Mary Babb Randolph Cancer Center
West Virginia University
Robert C. Byrd Health Sciences Center
P.O. Box 9300
1 Medical Center Drive
Room 2814 HSS
Morgantown, WV 26506
Phone: (304) 293-2980
Fax: (304) 293-4667
Email: sfrisch@hsc.wvu.edu

Research:

1. E1a. We have found a gene that universally reverses the transformation of human tumor cells, offering an alternative to the formidable challenge of specifically tailoring cancer therapies for each patient's tumor genotype.
   E1a profoundly re-programs tumor cell behavior in vitro and in vivo. First, E1a upregulates epithelial cell adhesion genes, causing a "mesenchymal-to-epithelial transition" - the reverse of epithelial cells' conversion into carcinoma cells. Secondly, E1a upregulates certain key pro-apoptotic genes. This sensitizes tumor cells to apoptosis in response to detachment from matrix ("anoikis", see below) as well as death ligands (e.g., TRAIL) and conventional chemotherapeutic drugs/DNA damaging agents. Thus, tumor cells with E1a are viable in culture but become epithelial and anchorage-dependent due to anoikis, thus failing to form tumors.
   Several phase I-II clinical trials using E1a gene therapy for breast, ovarian and head/neck cancer have been attempted, but the gene delivery approach is severely limited for cancer. We plan to identify genes or compounds that mimic the p300- or CtBP-inactivating effects of E1a and cause tumor suppression. These will be tested in preclinical and clinical trials for effectiveness against human neoplasia.
   
2. Anoikis. Our laboratory also discovered the phenomenon of "anoikis", which is defined as apoptosis that is suppressed by extracellular matrix. Epithelial cells (or tumor cells that have been converted to epithelial cells using E1a) that are released from high-turnover tissues are programmed to undergo anoikis. This response prevents the circulation and colonization of the released cells at inappropriate sites. Conversely, tumor cells must become resistant to anoikis for metastasis to succeed. From the basic research point of view, anoikis conceptually bridges the cell adhesion and the apoptosis fields. Most of the fundamental mechanisms underlying anoikis remain to be discovered, and this will involve the combination of insights into cytoskeletal mechanisms, signal transduction and perhaps specialized apoptotic mechanisms, all of which can be altered by oncogenes or tumor suppressor genes. In a larger sense, anoikis is a new phenotypic difference between epithelial cells and carcinoma cells that offers conceptually novel therapeutic possibilities. The mechanism of anoikis is a major focus of the laboratory.
   
3. Novel functions of death receptor-related apoptotic factors. We found that an adaptor protein for death receptors, FADD (FAS-associated death domain protein), resides in the nucleus, where it interacts with MethylCpG-Binding Domain protein-4 (MBD4). This provides a potential direct link between genome surveillance and apoptosis, which is being investigated. We also found that caspase-8 plays an important role in modulating cell motility and cell adhesion, through a novel pathway that is currently being elucidated.

Finally, we found that the direct effector molecule for FADD, caspase-8 has a novel and unexpected function in regulating cell adhesion, motility and cytokinesis. This is being pursued as well.

References:

• Huang X, Masselli A, Frisch SM, Hunton IC, Jiang Y, and Wang JY.  Blockade of tumor necrosis factor-induced Bid cleavage by caspase-resistant Rb.  J Biol Chem. 282: 29401-29413, 2007.
• Helfer B, Boswell BC, Finlay D, Cipres A, Vuori K, Bong Kang T, Wallach D, Dorfleutner A, Lahti JM, Flynn DC, and Frisch SM.  Caspase-8 promotes cell motility and calpain activity under nonapoptotic conditions.  Cancer Res. 66: 4273-4278, 2006.
• Bian D, Mahanivong C, Yu J, Frisch SM, Pan ZK, Ye RD, and Huang S.  The G12/13-RhoA signaling pathway contributes to efficient lysophosphatidic acid-stimulated cell migration.  Oncogene 25: 2234-2244, 2006.
• Frisch SM.  E1A as a tumor suppressor gene: commentary re S. Madhusudan et al. A multicenter Phase I gene therapy clinical trial involving intraperitoneal administration of E1A-lipid complex in patients with recurrent epithelial ovarian cancer overexpressing HER-2/neu oncogene.  Clin Cancer Res. 10: 2905-2907, 2004
• Screaton RA, Kiessling S, Sansom OJ, Millar CB, Maddison K, Bird A, Clarke AR, and Frisch SM. Fas-associated death domain protein interacts with methyl-CpG binding domain protein 4: a potential link between genome surveillance and apoptosis. Proc. Natl. Acad. Sci. 100: 5211-5216, 2003.
• Grooteclaes, M., Deveraux, Q., Hildebrand, J., Zhang, Q., Goodman, R. H. and Frisch, S.M. C-terminal binding protein corepresses epithelial and pro-apoptotic gene expression programs. Proc. Natl. Acad. Sci. 100: 4568-4573, 2003
• Zhang Q, Yoshimatsu Y, Hildebrand J, Frisch SM, Goodman RH.. Homeodomain interacting protein kinase 2 promotes apoptosis by downregulating the transcriptional corepressor CtBP. Cell 115:177-86, 2003
• Frisch, S.M. and Mymyrk, J. Adenovirus E1a: paradox and paradigm. Nature Reviews Molec. Cell Biol 3: 441-452, 2002