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 has made several seminal contributions to an understanding of the in vivo functions of the TGFβ signaling pathway in driving tumorigenesis and angiogenesis. TGF-β signal transduction has been well characterized in vitro, but much still remains unresolved concerning functional interactions that occur between this signaling pathway and other biological pathways in vivo. Over the last two decades, it has become clear that TGFβ signaling is a driver in several human diseases, including cancer, fibrosis, vascular disease and inflammation. TGF-β signaling is often elevated in the pathological state and exacerbates that state. The importance of TGF-β in promoting 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 to such drugs will vary due to somatic genetic differences intrinsic to that tumor and because of germline genetic variants that affect the tumor microenvironment. Our lab uses an integrated molecular and biological approach utilizing mouse models of cancer and cancer therapeutics, developmental biology, mouse and human genetics, together with bioinformatics and in vitro cell and molecular biology, in order to study these mechanisms of TGF-β action during in vivo angiogenesis and tumorigenesis, and to investigate how genetic variants influence pathology. In the cancer field we collaborate with drug companies to investigate preclinical mechanisms of novel TGFβ blockade drugs. We currently study the potential of TGFβ blockade to enhance cancer immunotherapy. We also study rare diseases caused by mutations in genes encoding components of the TGFβ/BMP signaling pathway, such as the vascular disorder, Hereditary Hemorrhagic Telangiectasia, in order to understand how interacting genetic variants influence the severity of this human disease, and to gain insight into mechanisms of in vivo angiogenesis and vascular stability in human. A deeper understanding of the genes responsible for variable outcome of TGFβ pathway manipulation will provide insights into molecular mechanisms for variable phenotypes, and might contribute to development of novel drugs or drug-dosing regimens for a number of diseases that involve the TGFβ/BMP signaling pathway.

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.