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Hedgehog signaling in cancer

We have demonstrated a role for Hedgehog pathway activity in the continuing growth of basal cell carcinoma, medulloblastoma, and other cancers associated with loss-of-function mutations of the tumor suppressor, Patched, or gain-of-function mutations of the proto-oncogene Smoothened (see Hedgehog Signal Transduction). The cyclopic phenotype of Shh knockout mice led us to identify the teratogenic plant compound cyclopamine as a specific antagonist of Hh pathway activity, and to show that cyclopamine acts by binding to a critical component in Hh signal transduction, the 7TM protein Smoothened. We have established the feasibility and methods for identification and development of drugs that can be used for pathway blockade as a novel therapeutic approach to these cancers. We demonstrated the feasibility of using cyclopamine or other mimics of cyclopamine action as non-toxic therapeutic agents in the treatment of Hh-dependent cancers such as medulloblastoma, and on January 31, 2012 the FDA approved Vismodegib, a cyclopamine mimic, for use in aggressive and metastatic forms of basal cell carcinoma.

Building on our understanding of the role of hedgehog signaling in tissue renewal, we are addressing long-standing questions regarding the possible stem cell origin of cancer and the influence of stromal niche signals in cancer. We have also discovered that Hedgehog response in the stroma of malignancies not associated with pathway activating mutations can instead restrain tumor growth and progression, particularly in malignancies arising from endodermal organs. Our studies and others thus indicate a surprisingly general cancer-restraining effect of stromal cells in endodermally-derived malignancies such as invasive urothelial carcinoma (IUC), pancreatic ductal adenocarcinoma (PDAC) and colitis-associated colon adenocarcinoma.  This effect contrasts with the growth-promoting activity of the Hedgehog pathway in primary cells of ectodermally derived cancers such as basal cell carcinoma and medulloblastoma, and may be mediated by Hedgehog-induced stromal differentiation signals such as Bmp4/Bmp5.  These findings suggest novel approaches to cancer therapies that harness the cancer-restraining effects of stromally-derived differentiation signals.

We continue to investigate the mechanistic basis for cancer growth -restraining/-promoting effects of Hedgehog signaling in endodermally or ectodermally derived organs and to explore germ layer derivation as a determinant for the role of Hedgehog pathway activity in cancer growth.

Select Reviews and Publications:

Chiang, C., Litingtung, Y., Lee, E., Young, K.E., Corden, J.L.,Westphal, H., Beachy, P.A.  Cyclopia and defective axial patterning in mice lacking Sonic Hedgehog gene function.  Nature 383:407-413  (1996). Pubmed

Cooper, M.K., Porter, J.A., Young, K.E., Beachy, P.A.  Teratogen-mediated inhibition of target tissue response to Shh signaling.  Science 280:1603-1607 (1998). Pubmed

Taipale, J., Chen, J.K., Cooper, M.K., Wang, B., Mann, R.K., Milenkovic, L., Scott, M.P., Beachy, P.A. Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine.  Nature 406:1005-1009  (2000). Pubmed

Chen, J.K., Taipale, J., Cooper, M.K., Beachy, P.A.  Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened.  Genes & Dev. 16: 2743-2748  (2002). Pubmed

Chen, J.K., Taipale, J., Young, K.E., Maiti, T., Beachy, P.A.  Small molecule modulation of Smoothened activity.  Proc Natl Acad Sci 99(22):14071-6  (2002).  Pubmed

Berman, D.M., Karhadkar, S.S., Hallahan, A.R., Pritchard, J.I., Eberhart, C.G., Watkins, D.N., Chen, J.K., Cooper, M.K., Taipale, J., Olson, J.M., Beachy, P.A. Medulloblastoma growth inhibition by Hedgehog pathway blockade.  Science 297(5586):1559-61 (2002). Pubmed

Shin, K., Lim, A., Odegaard, J.I., Honeycutt J.D., Kawano, S., Hsieh, M.H., Beachy, P.A. Cellular origin of bladder neoplasia and tissue dynamics of its progression to invasive carcinoma.  Nat Cell Biol. 16(5):469-78 (2014). PMC4196946. Pubmed

Shin, K., Lim, A., Zhao, C., Sahoo, D., Pan, Y., Spiekerkoetter, E., Liao, J.C., Beachy, P.A. Hedgehog signaling restrains bladder cancer progression by eliciting stromal production of urothelial differentiation factors. Cancer Cell 26:4:521-533 (2014). Pubmed

Lee, J.J., Perera, R.M., Wang, H., Wu, D.C., Liu, X.S., Han, S., Fitamant, J., Jones, P.D., Ghanta, K.S., Kawano, S., Nagle, J.M., Deshpande, V., Boucher, Y., Kato, T., Chen, J.K., Willmann, J.K., Bardeesy, N., Beachy, P.A. Stromal response to Hedgehog signaling restrains pancreatic cancer progression. Proc Natl Acad Sci 111(30):E3091-100 (2014). Pubmed

Lee, J.J., Rothenberg, M.E., Seeley, E.S., Zimdahl, B., Kawano, S., Lu,  W.-J., Shin, K., Sakata-Kato, T., Chen, J.K., Diehn, M., Clarke, M.F., Beachy, P.A. Control of inflammation by stromal Hedgehog pathway activity restrains colitis. Proc Natl Acad Sci113(47):E7545-53 (2016).   Pubmed

Roberts, K.J., Kershner, A.M., Beachy, P.A. The Stromal Niche for Epithelial Stem Cells: A Template for Regeneration and a Brake on Malignancy. Cancer Cell, 32(4):404-410 (2017).  Pubmed

 

 

 

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