Cell and Developmental Biology University of Michigan

Research

Develop novel therapies for the malignant brain tumors based on depletion of cancer stem like cells.

Medulloblastoma (MB) and glioblastoma (GBM) are the most common malignant brain tumors in children and adults, respectively. There is accumulated evidence showing that a small population of cancer stem cells (CSCs) within cancers is responsible for tumor propagation, including MB and GBM. The CSC hypothesis challenges traditional therapeutic concepts, suggesting that only by removing CSCs within a tumor can the cancer be cured. Our goal is to develop novel therapies for the malignant brain tumors MB and GBM based on the depletion of CSCs. It has been shown that the Notch singling pathway regulates normal stem cells in the central nervous system (CNS), and that MB and GBM contain CSCs with higher Notch activity. We have demonstrated recently that Notch pathway inhibition depletes CSCs and blocks engraftment of MB and GBM cells. This work represents a strong demonstration of a chemotherapeutic agent that can target CSCs in solid tumors. Our current projects include exploring the translational therapeutic application of Notch pathway blockade into clinic, and examining the mechanism by which Notch, SHH, Wnt and other signaling pathways that regulate these brain CSCs.

Lab Members

• Thant Zhu
  Research Fellow
• Mary Soules
  Research Lab Technician
• Mikel Gurrea
  Graduate Student
• Peng Xu
  Graduate Student
• Mark Costello
  Undergradate Student
• Callie Flack
  Undergradate Student
• Christina Lineback
  Undergradate Student
• Caroline Talsma
  Undergradate Student

Publications

Representative Publications

1. Fan X*, Khaki L, Zhu TS, Soules ME, Talsma CE, Gul N, Koh C, Zhang J, Li YM, Maciaczyk J, Nikkhah G, DiMeco F, Piccirillo S, Vescovi AL, Eberhart CG. Notch Pathway Blockade Depletes CD133-Positive Glioblastoma Cells and Inhibits Growth of Tumor Neurospheres and Xenografts. Stem Cells (in press) 2009, (*: Corresponding Author).
2. Mullendore ME, Koorstra JB, Li YM, Offerhaus GJ, Fan X, Henderson CM, Matsui W, Eberhart CG, Maitra A, Feldmann G. Ligand-dependent Notch signaling is involved in tumor initiation and tumor maintenance in pancreatic cancer. Clinical Cancer Research, Apr 1;15(7):2291-301, 2009.
3. Fan X*, Eberhart CG*. Medulloblastoma Stem Cells. Journal of Clinical Oncology, Jun 10;26(17):2821-7, 2008 (*: Corresponding Author).
4. Li T, Wen H, Brayton C, Das P, Smithson LA, Fauq A, Fan X, Crain BJ, Price DL, Golde TE, Eberhart CG, Wong PC. EGFR and notch pathways participate in the tumor suppressor function of gamma -secretase. Journal of Biological Chemistry, Nov 2;282(44):32264-73, 2007.
5. Bar EE, Chaudhry A, Lin A, Fan X, Schreck K, Matsui W, Vescovi AL, Piccirillo S, Dimeco F, Olivi A, Eberhart CG. Growth Inhibition of GBM and Glioma-Associated Cancer Stem Cells by Cyclopamine. Stem Cells, Oct;25(10):2524-33, 2007.
6. Dang L, Fan X (co-first author), Chaudhry A, Wang M, Gaiano N, Eberhart CG. Notch3 Signaling Initiates Choroid Plexus Tumor Formation. Oncogene, Jan 19;25(3):487-91, 2006.
7. Fan X, Matsui W, Khaki L, Stearns D, Chun J, Li YM, Eberhart CG. Notch Pathway Inhibition Depletes Stem-Like Cells and Blocks Engraftment in Embryonal Brain Tumors. Cancer Research, August 1; 66(15):7445-52, 2006.
8. Li Y, Lal B, Kwon S, Fan X, Saldanha U, Reznik TE, Kuchner EB, Eberhart C, Laterra J, Abounader R. The scatter factor/hepatocyte growth factor: c-met pathway in human embryonal central nervous system tumor malignancy. Cancer Research, Oct 15; 65(20):9355-62, 2005.
9. Fan X, Mikolaenko I, Elhassan I, Ni X, Wang Y, Ball D, Brat DJ, Perry A, Eberhart CG. Notch1 and Notch2 have opposite effects on embryonal brain tumor growth. Cancer Research, Nov 1;64 (21):7787-93, 2004. (Featured on cover).
10. Fan X, Wang Y, Kratz J, Brat DJ, Robitaille Y, Moghrabi A, Perlman EJ, Dang CV, Burger PC, Eberhart CG. hTERT gene amplification and increased mRNA expression in central nervous system embryonal tumors. American Journal of Pathology, Jun;162 (6):1763-9, 2003.