Romnes
Professor of Oncology and Medical Genetics
B.S., 1973, Chemistry, Rensselaer Polytechnic Institute, NY
Ph.D., 1979, Biochemistry, Cornell University, NY
Postdoctoral research: Massachusetts Institute of Technology
and Harvard University
Office: 320 McArdle Laboratory
Telephone: Office - (608) 263-2890; Lab - (608) 262-8854
Email: fmhoffma@facstaff.wisc.edu
Lab Home Page
Research Interests: Chemical genetic and genetic approaches to study TGF-beta signal transduction
Research Description: To identify functionally important molecules on the TGF-beta signal transduction pathway in either normal cells or tumor cells, we are taking a chemical genetic approach that identifies key genes through screening of large libraries of chemical ligands. Chemical ligands are identified in biological assays as inhibitors of the process, e.g., a ligand that inhibits or stimulates the growth of tumor cells relative to normal cells. The approach is analogous to classical genetic phenotype-driven screens. Rather than screening for a phenotypic change after random mutagenesis, one screens for the phenotypic change after application of a library of chemical compounds. Rather than identifying the mutant gene by positional cloning, one uses the chemical inhibitor as a ligand to isolate the protein target and obtains the gene through knowledge of the protein product. The chemical ligands can be used to test the role of the target in a variety of cell culture and animal models of normal cell functions or disease processes.
The TGF-beta signal transduction pathway plays several key roles in the development and progression of human tumors. The proliferation of normal epithelial and lymphoid cells is strongly inhibited by TGF-beta but cancer cells lose their ability to be growth inhibited by TGF-beta or, in some cases, alter the pathway such that TGF-beta stimulates proliferation of the cancer cell. Mutations in TGF-beta receptors and Smad proteins have been associated with a large number of human tumors. For example, 50% of human pancreatic tumors are mutant for Smad4, a key molecule in the TGF-beta signal transduction pathway. In collaboration with Drs. Norman Drinkwater and John Niederhuber, we are using gene targeting of Smad4 in the mouse to generate a better mouse model of pancreatic cancer. Having lost or altered their own response to TGF-beta, many tumors express TGF-beta in order to facilitate tumor invasiveness and to protect the tumor from attack by the immune system. The latter is consistent with the observation that TGF-beta is the most potent immunosuppressive factor known. Agents that inhibit TGF-beta signaling could provide novel therapeutic strategies to reduce tumor invasiveness and to make tumors more susceptible to attack by the patient's own immune system.
Although neutralizing antibodies to TGF-beta, TGF-beta antisense expression and soluble TGF-beta receptors have been used to demonstrate the importance of TGF-beta signaling in several animal models of cancer, these approaches do not lend themselves to use as human therapeutics. The recent elaboration of the TGF-beta signal transduction pathway, including the receptors, the Smad proteins and several Smad-interacting transcription factors, provides an array of new targets that could be potential sites for intervention. There are currently no therapeutic agents that act on these targets in the TGF-beta pathway.
Several functional interactions on the TGF-beta signaling pathway lend themselves to screening for small molecule inhibitors including phosphorylation of Smad by the receptor, Smad-SARA interactions, Smad-Smad interactions, and Smad interactions with transcriptional regulators. We are establishing a number of biochemical and cell based assays to screen libraries of chemical compounds (natural product and synthetic) and phage display libraries for disruption of these interactions.
Hoffmann, F. M., Cui, Q., Lim, S. K., and Zhao, B. M. Targeting Smad-dependent TGF-b Signaling with Peptide Aptamers. In: S. Jakowlew (Ed.), Transforming Growth Factor-b in Cancer Therapy, Volume II, Chapter 45. Totowa, NJ: Humana Press, 2008.
Yang, B., O’Herrin, S. M., Wu, J., Reagan-Shaw, S., Ma, Y., Bhat, K. M. R., Gravekamp, C., Setaluri, V., Peters, N., Hoffmann, F. M., Peng, H., Ivanov, A. V., Simpson, A. J. G., and Longley, B. J. MAGE-A, mMage-b, and MAGE-C Proteins Form Complexes with KAP1 and Suppress p53-Dependent Apoptosis in MAGE-Positive Cell Lines. Cancer Res., 67: 9954-9962, 2007.
Ahmed, A., Peters, N. R., Fitzgerald, M. K., Watson, J. A. Jr., Hoffmann, F. M., and Thorson, J. S. Colchicine Glycorandomization Influences Cytotoxicity and Mechanism of Action. J. Am. Chem. Soc., 128: 14224-14225, 2006.
Lim, S. K., and Hoffmann, F. M. Smad4 Cooperates with Lymphoid Enhancer-binding Factor 1/T Cell-specific Factor to Increase c-myc Expression in the Absence of TGF-b Signaling. Proc. Natl. Acad. Sci. USA, 103: 18580-18585, 2006.
Zhao, B. M., and Hoffmann, F. M. Inhibition of Transforming Growth Factor-b1-induced Signaling and Epithelial-to-Mesenchymal Transition by the Smad-binding Peptide Aptamer Trx-SARA. Mol. Biol. Cell, 17: 3819-3831, 2006.
Cui, Q., Lim, S. K., Zhao, B., and Hoffmann, F. M. Selective Inhibition of TGF-β Responsive Genes by Smad-interacting Peptide Aptamers from FoxH1, Lef1 and CBP. Oncogene, 24: 3864-3874, 2005.
Langenhan, J. M., Peters, N. R., Guzei, I. A., Hoffmann, F. M., and Thorson, J. S. Enhancing the Anticancer Properties of Cardiac Glycosides by Neoglycorandomization. Proc. Natl. Acad. Sci. USA, 102: 12305-12310, 2005.
Martin, M., Ahern-Djamali, S. M., Hoffmann, F. M., and Saxton, W. M. Abl Tyrosine Kinase and Its Substrate Ena/VASP Have Functional Interactions with Kinesin-1. Mol. Biol. Cell, 16: 4225-4230, 2005.
Ahern-Djamali, S. M., Bachmann, C., Hua, P., Reddy, S. K., Kastenmeier, A. S., Walter, U., and Hoffmann, F. M. Identification of Profilin and src Homology 3 Domains as Binding Partners for Drosophila enabled. Proc. Natl. Acad. Sci. USA, 96: 4977-4982, 1999.
Fogarty, F. J., Juang, J.-L., Petersen, J., Clark, M. J., Hoffmann, F. M., and Mosher, D. F. Dominant Effects of the bcr-abl Oncogene on Drosophila Morphogenesis. Oncogene, 18: 219-232, 1999.
Johnson, K., Kirkpatrick, H., Comer, A., Hoffmann, F. M., and Laughon, A. Interactions of Smad Complexes with Tripartite DNA-binding Sites. J. Biol. Chem., 274: 20709-20716, 1999.
Juang, J.-L., and Hoffmann, F. M. Drosophila Abelson Interacting Protein (dAbi) Is a Positive Regulator of Abelson Tyrosine Kinase Activity. Oncogene, 18: 5138-5147, 1999.
Ahern-Djamali, S. M., Comer, A. R., Bachmann, C., Kastenmeier, A. S., Reddy, S. K., Beckerle, M. C., Walter, U., and Hoffmann, F. M. Mutations in Drosophila Enabled and Rescue by Human Vasodilator-stimulated Phosphoprotein (VASP) Indicate Important Functional Roles for Ena/VASP Homology Domain 1 (EVH1) and EVH2 Domains. Mol. Biol. Cell, 9: 2157-2171, 1998.
Chen, Y., Riese, M. J., Killinger, M. A., and Hoffmann, F. M. A Genetic Screen for Modifiers of Drosophila decapentaplegic Signaling Identifies Mutations in punt, Mothers against dpp and the BMP-7 Homologue, 60A. Development, 125: 1759-1768, 1998.
Comer, A. R., Ahern-Djamali, S. M., Juang, J.-L., Jackson, P. D., and Hoffmann, F. M. Phosphorylation of Enabled by the Drosophila Abelson Tyrosine Kinase Regulates the in Vivo Function and Protein-Protein Interactions of Enabled. Mol. Cell. Biol., 18: 152-160, 1998.
Horsfield, J., Penton, A., Secombe, J., Hoffmann, F. M., and Richardson, H. decapentaplegic Is Required for Arrest in G1 Phase during Drosophila Eye Development. Development, 125: 5069-5078, 1998.
