Our research group is interested in how Transforming Growth Factor- b (TGF-b) and its signaling pathway regulate normal embryonic development and how the effects of this signaling network are perturbed in disease processes in vivo, particularly in cancer. TGF-b signaling is essential for normal vascular development of the embryo. In the adult it is an important regulator of homeostasis for many tissues, including epithelial, endothelial and immune. TGF-b is induced in response to physical, chemical, or radiation damage, where it contributes to re-establishment of normal tissue dynamics. In disease processes, however, TGF-b signaling is often switched on in a dysregulated fashion and stimulates disease progression. This is particularly true during progression of cancer and fibrosis, as well as in several vascular diseases. This detrimental elevation in TGFb signaling in human disease has prompted biotech and pharmaceutical companies to develop inhibitors against this signaling pathway. Anti-TGFb drug trials for oncology and fibrosis applications are ongoing around the World.
Our lab has shown that TGF-b is essential for normal angiogenesis (vascular development), and that it promotes tumor progression and tumor metastasis. Interestingly we have shown that the effect of reducing TGF-b signaling in vivo is highly variable between individuals, and that this is due to normal inter-individual genetic variation that occurs in both mouse and human populations. We are identifying and characterizing the variant genes that modify the effects of TGF-b signaling on vascular development and remodeling that occurs during embryogenesis and during malignant tumor progression. Characterization of these novel genes will provide new insight into the molecular mechanisms that regulate TGF-b biology in vivo, and may provide novel drug targets for disease treatment. This information may also allow us to predict disease risk, severity or prognosis, or to predict how individual patients might respond to TGF-b inhibitory drugs.
This work is relevant to human vascular disease, since humans that have mutations in genes of the TGF-b pathway have vascular complications, such as Familial Pulmonary Arterial Hypertension (FPAH), Hereditary Hemorrhagic Telangiectasia (HHT), and Loeys-Dietz Syndrome (LDS). It is also important to cancer, since we know that in some tumor types, TGF-b signaling components are tumor suppressors but that in other tumor types TGF-b can promote malignant progression and metastasis, and that TGF- b1 effects are dependent on genetic context.
The approaches that we take involve generation and analysis of transgenic and gene knock-out mice that over-express or ablate TGF-b components. We also study the effects of innate genetic variation on the phenotypes of these transgenic and gene knock-out mice. We have found that the phenotypes can vary enormously depending on the presence of different variants of endogenous “modifier” genes within the genome. Again, this reflects the human condition, where genetic variants in other genes can alter the severity of phenotypes for FPAH, HHT and LDS. We have analyzed this innate genetic variation by undertaking large genetic crosses, and also by selective breeding of endogenous gene variants onto different mouse strain backgrounds to produce “congenic” mice. We then analyze these gain-of-function, loss-of-function and congenic animals for perturbations in embryonic development, tumor induction, tumor biology, as well as investigating effects on stem cells that give rise to both the vascular system and to tumors. Molecular and biological analysis of these mice, and cells derived from them, allows us to draw conclusions about the function of the modifier genes and how these contribute to vascular biology, cancer and other diseases. We also collaborate with clinicians and human geneticists to address how these syntenic genetic variants influence human disease.
What is the genetic makeup of these genetic modifier loci? Why do these loci influence so many diseases (cancer, vascular disease, inflammation, asthma)? What is the biological basis for the action of the modifiers - Action on tumor angiogenesis? Endothelial progenitor cells? Tumor stem cells? Immune system? What is the molecular basis for functional interaction between the TGF-b1 signaling pathway and the modifier genes?
Finally, we are administering to mice, novel drugs that are targeted against the TGF-b signaling components to investigate their utility as anti-cancer or anti-angiogenic agents in vivo. The findings have broad implications to major human diseases that include a vascular component and/or involve TGF-b, such a as cancer, athersclerosis and inflammation.
Akhurst, R.J., Lehnert, S.A., Faissner, A. and Duffie, E. (1990) TGF beta in murine morphogenetic processes: the early embryo and cardiogenesis. Development, 108, 645-56.
Dickson, M.C., Martin, J.S., Cousins, F.M., Kulkarni, A.B., Karlsson, S. and Akhurst, R.J. (1995) Defective haematopoiesis and vasculogenesis in transforming growth factor-beta 1 knock out mice. Development, 121, 1845-54.
Cui, W., Fowlis, D.J., Bryson, S. Duffie, E., Ireland, H., Balmain, A. and Akhurst, R.J. TGF b1 inhibits the formation of benign skin tumours but enhances progression to invasive spindle carcinomas in transgenic mice. Cell 86: 531-542, 1996.
Bonyadi, M., Rusholme, S.A.B., Cousins, F.M., Su, H., Biron, C., Farrall M. and Akhurst, R.J. . Mapping of a major genetic modifier of embryonic lethality in TGFb1-deficient mice. Nature Genetics 15: 207-211, 1997.
Portella, G., Cumming S.A., Liddell, J., Cui, W., Ireland, H., Akhurst, R.J., and Balmain, A. TGFb is essential for spindle cell conversion of mouse skin carcinoma in vivo: implications for invasion. Cell Growth Diff. 9: 393-4041, 1998.
Oft, M., Akhurst, R.J. and Balmain, A. Metastasis is driven by sequential elevation of H-ras and Smad2 levels. Nature Cell Biology, 4: 487-494, 2002.
Ewan, K. B., Henshall-Powell, R. L. , Ravani, S. A., Parjares, M. J. , Arteaga, C. Warters, , R., Akhurst, R.J. and Barcellos-Hoff, M. H. Depletion of Transforming Growth Factor- 1 Blocks Radiation-Induced Apoptosis and p53 Response Cancer. Res 62, 5627-31, 2002.
Tang, Y., McKinnon, M.L., Leong, L.M., Rusholme, S.A.B., Wang, S. and Akhurst, R.J. Genetic modifiers interact with maternal determinants in vascular development of Tgfb1-/- mice Human Molecular Genetics 12, 1579-1679, 2003.
Akhurst, R. J. TGFb signaling in health and disease. Nature Genetics 36, 790-792, 2004.
Tang, Y., Lee, K.S., Yang, H.T., Logan, D.W., Wang, S., McKinnon, M.L., Holt, L.J., Condie, A., Luu, M.T. and Akhurst R. J. Epistatic interactions between modifier genes confer strain-specific redundancy for Tgfb1 in developmental angiogenesis. Genomics 85,60-70, 2005.
Poon, E., Clermont, F., Firpo, M.T. and Akhurst, R.J. TGFb inhibition of yolk sac-like differentiation of human embryonic stem cell-derived embryoid bodies illustrates differences between early mouse and human development. J. Cell Sci. 119, 759-68, 2006.
Lacher, M.D., Tiirikainen, M.I., Saunier, E.F., Christian, C., Anders, M., Oft, M., Balmain, A., Akhurst, R.J. and Korn, W.M. TGFb Receptor Inhibition Enhances Adenoviral Infectivity of Carcinoma Cells Via Up-regulation of CAR in Conjunction with Reversal of Epithelial-Mesenchymal-Transition. Cancer Res. 66:1648-57, 2006.
Mao, J-H., Saunier, E.F., de Koning, J., McKinnon, M.M., Higgins, M.N., Nicklas, K., Yang, H-T., Balmain, A. and Akhurst, R.J. Genetic variants of Tgfb1 act as context-dependent modifiers of mouse skin tumor susceptibility. Proc. Natl. Acad. Sci ( USA) 103(21):8125-30, 2006.
Derynck, R. and Akhurst, R.J. Differentiation plasticity regulated by TGF-b family proteins in development and disease. Nature Cell Biol, 9( 9): 1000-4, 2007.
Kang, J.S., Saunier, E.F., Akhurst, R.J. and Derynck, R. The type I TGF-b receptor is covalently modified and regulated by sumoylation. Nature Cell Biology 10(6):654-64, 2008.