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Akhurst Lab

akhurst_rosemary

Full Biosketch: Rosemary J. Akhurst, PhD
Professor In Residence, Helen Diller Family Comprehensive Cancer Center and Department of Anatomy, UCSF; Director, Preclinical Therapeutics Core Facility, Helen Diller Family Comprehensive Cancer Center, UCSF

rakhurst@cc.ucsf.edu

Phone:
(415) 514-0215 (direct)
(415) 502-4180 (admin. asst.)
(415) 502-3179 (fax)

1450 3rd St., MC 0128; PO Box 589001
San Francisco, CA 94158-9001

deliveries: 1450 3rd Street, HD-320; San Francisco, CA 94158

Research Summary

The Akhurst lab investigates the role that TGF-β plays in tumorigenesis and angiogenesis. It is highly likely that TGF-β inhibitors will be successful for certain clinical applications making this area of study highly relevant to translational research.

Over the last two decades it has become increasingly apparent that the TGF-β pathway is a central player in several human diseases, including cancer, fibrosis and vascular diseases. TGF-β signaling is often elevated in the pathological state. The importance of TGF-β1 in driving tumor progression and metastasis is now widely recognized, and pharmaceutical companies have developed a panel of TGF-β inhibitory drugs for cancer treatment, some of which are in clinical trial. Despite these developments, the response of each tumor type will be different since the signaling pathway can have tumor suppressing and tumor progressing activity, and TGF-β can affect both tumor cells as well as all cells of the tumor microenvironment. A deeper understanding of how manipulation of the TGF-β signaling pathway affects in vivo outcomes in mouse models and in patients is essential to optimize drug dosing regimens and minimize potential side-effects.

An integrated molecular and biological approach is warranted because, although the biochemistry of TGF-β signal transduction has been well characterized in vitro, much remains unresolved concerning functional interactions that occur between this signaling pathway and other biological pathways in vivo. We are taking multiple complementary approaches including mouse tumorigenesis and developmental biology, mouse and human genetics, together with in vitro cell and molecular analysis to study TGF-β action during angiogenesis and tumorigenesis.

Representative publications:

  1. Lehnert, S.A., and Akhurst, R.J. Embryonic expression pattern of  TGFβ type-1 RNA suggests both paracrine and autocrine mechanisms of action. Development, 104: 263-273, 1988.
  2. Akhurst, R.J., Fee, F., and Balmain, A. Localized production of TGF-β mRNA in tumour promoter-stimulated mouse epidermis. Nature, 331: 363-365, 1988.
  3. Dickson, M.C., Martin, J. S., Cousins, F., Kulkarni, A. B., Karlsson, S. and Akhurst, R. J. Defective haematopoiesis and vasculogenesis in TGFb1 knockout mice. Development 121: 1845-1854, 1995.
  4. Cui, W., Fowlis, D.J., Bryson, S. Duffie, E., Ireland, H., Balmain, A. and Akhurst, R.J. TGFb1 inhibits the formation of benign skin tumours but enhances progression to invasive spindle carcinomas in transgenic mice. Cell 86: 531-542, 1996.
  5. 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.
  6. 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.
  7. 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.
  8. 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.
  9. 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.
  10. Harradine, K.A., Ridd, K, Saunier, E.F., Clermont, F.F., Perez-Losada, J., Moore, D. H., Epstein Jr., E. H. Bastian, B. C. and Akhurst, R. J. Elevated cutaneous Smad activation associates with enhanced skin tumor susceptibility in organ transplant recipients. Clinical Cancer Research. 15:5101-7, 2009.
  11. Akhurst, R. J. Taking thalidomide out of rehab. (2010) Nature Medicine 16(4):370-2.  2010.
  12. Connolly, E.C., Saunier, E.F., Quigley, D., Luu, M.T., De Sapio, A., Hann, B., Yingling, J.M., Akhurst, R. J. Outgrowth of Drug-Resistant Carcinomas Expressing Markers of Tumor Aggression after Long-term TβRI/II Kinase Inhibition with LY2109761. Cancer Research 71(6):2339-49, 2011.
  13. Bouquet, F., Pal, A., Pilones, K.A., Demaria, S., Hann, B., Akhurst, R.J., Babb, R. Lonning, S. M. DeWyngaert, K., Formenti, S., and Barcellos-Hoff, M-H. TGFb1 Inhibition Increases the Radiosensitivity of Breast Cancer Cells In Vitro and Promotes Tumor Control by Radiation In Vivo. Clinical Cancer Research. 17(21):6754-65, 2011.
  14. Arnold, T., Ferrero, G., Qiu, H., Phan, I., Akhurst, R.J., Huang, E. and Reichardt, L. Defective retinal vascular endothelial cell development as a consequence of impaired Integrin β8-mediated activation of transforming growth factor-β.  J. Neuroscience. 32(4):1197-206, 2012.
  15. Lamouille, S., Connolly, E., Smyth, J., Akhurst, R. J. and Derynck, R. TGF-β-induced activation of mTOR complex 2 drives epithelial-mesenchymal transition and invasion. J. Cell Sci. 125:1259-73, 2012.
  16. Benzinou, M., Clermont, F. F., Letteboer, T. G., Kim, H.J., Espejel, S., Harradine, K. A., Arbelaez, J., Luu, M. T., Roy, R., Quigley, D., Higgins, M.N., Zaid, M., Aouizerat, B., Ploos van Amstel, J. K. , Giraud, S. , Dupuis-Girod, S., Lesca, G., Plauchu, H., Hughes, C.C., Westermann, C.J.J. and Akhurst, R.J. (2012) Mouse and human strategies identify PTPN14 as a modifier of angiogenesis and Hereditary Hemorrhagic Telangiectasia. Nature Communications, 3: 616, 1-9, 2012.
  17. Freimuth, J., Clermont, F.C., Huang, X. Z., de Sapio, A., Tokuyasu, T., Sheppard, D., Akhurst, R.J. "Epistatic interactions between Tgfb1 and genetic loci, Tgfbm2 and Tgfbm3, determine susceptibility to an asthmatic stimulus. Proc. Natl. Acad. Sci (USA) under minor revision. 2012.
  18. Akhurst, R.J. and Hata, A. Targeting the TGF-β signaling pathway in disease. Nature Reviews in Drug Development in press, 2012.
  19. Akhurst, R. J. The paradoxical TGFβ vasculopathies. Nature Genetics in press, 2012.