Xing Fan, M.D., Ph.D.
Assistant Professor of Neurosurgery
and Cell & Developmental Biology
109 Zina Pitcher Place
5018 Biomedical Sciences Research Bldg (BSRB)
Phone number: (734) 615-7266
Fax number: (734) 7322
Email: xingf@med.umich.edu

Go to Xing Fan's Research Lab

 Xing Fan

Research Focus:

Medulloblastoma (MB) and glioblastoma (GBM) are the most common malignant brain tumors in children and adults, respectively. As these patients’ overall survival is very poor, new therapeutic strategies are desperately needed. There is emerging evidence showing that a small population of cancer stem cells (CSCs) within cancers is responsible for tumor formation. Recent published data also showed that MB and GBM contain such CSCs. 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 in established MB cell lines. Specifically, we showed that: 1) CSCs in MB cell lines have elevated levels of Notch activity, and require this pathway for survival and proliferation. 2) Activation of Notch2 in MB cultures increased the CSC fraction. 3) Pharmacological inhibition of Notch using gamma-secretase inhibitors depleted CSCs via reduced proliferation, neuronal differentiation and apoptosis. 4) Notch blockade preferentially reduced the CSC fraction, as viable populations of better-differentiated cells continued to slowly grow, but were unable to efficiently initiate soft agar colonies or tumor xenografts. This work represents a strong demonstration of a chemotherapeutic agent that can target CSC in solid tumors. We therefore well positioned to further address this exciting new area of cancer biology.

Recent studies showed that MB and GBM primary cultures mimic more closely the original tumors. In addition, because these tumors can be grown in culture using the neurosphere system developed to manipulate neural stem cells, they provide an ideal system for testing the role the stem cell in cancer. Our current projects include exploring the translational therapeutic application of Notch pathway blockade into clinic, and examining the mechanism by which Notch signaling pathway regulates these brain CSCs.

Selected Publications:

  1. Fan X, Eberhart CG. Medulloblastoma Stem Cells. Journal of Clinical Oncology (Invited Review, in press 2008)
  2. 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.
  3. 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.
  4. 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).
  5. 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.
  6. Fan X, Aalto Y, Sanko SG, Knuutila S, Klatzmann D, Castresana JS.  Genetic profile, PTEN mutation and therapeutic role of PTEN in glioblastomas. International Journal of Oncology, Nov;21(5):1141-50, 2002.
  7. Fan X, Munoz J, Sanko SG, Castresana JS. PTEN, DMBT1, and p16 alterations in diffusely infiltrating astrocytomas. International Journal of Oncology, Sep;21(3):667-74, 2002.
  8. Fan X, Inda MM, Tunon T, Castresana JS. Improvement of the methylation specific PCR technical conditions for the detection of p16 promoter hypermethylation in small amounts of tumor DNA. Oncology Reports, Jan-Feb;9(1):181-183, 2002.
  9. Fan X, Furnari FB, Cavenee WK, Castresana JS. Non-isotopic silver-stained SSCP is more sensitive than automated direct sequencing for the detection of PTEN mutations in a mixture of DNA extracted from normal and tumor cells. International Journal of Oncology, 18: 1023-1026, 2001.
  10. Fan X, Paetau A, Aalto Y, Valimaki M, Sane T, Poranen A, Castresana JS, Knuutila S. Gain of Chromosomes 3 and 22q and Loss of Chromosome 13q Are Frequent Copy Number Changes in Pituitary Adenomas. Cancer Genetics and Cytogenetics, 128: 97-103, 2001.
  11. Fan X, Gómez L, Sierrasesúmaga L, Nistal M, Castresana JS. Lack of gene amplification as a mechanism of CDK4 activation in human neuroblastoma. Oncology Reports, 6:647-650, 1999.
  12. Fan X, Gómez L, Nistal M, Sierrasesúmaga L, Castresana JS. Differential polymerase chain reaction: a technical comparison of three methods for the detection of CDK4 gene amplification in glioblastomas. International Journal of Oncology, 13:963-966, 1998.
  13. 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, 25(10):2524-33, 2007
  14. 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.
  15. 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.
  16. Inda MM, Perot C, Guillaud-Bataille M, Danglot G, Rey JA, Bello MJ, Fan X, Eberhart C, Zazpe I, Portillo E, Tunon T, Martinez-Penuela JM, Bernheim A, Castresana JS. Genetic heterogeneity in supratentorial and infratentorial primitive neuroectodermal tumours of the central nervous system. Histopathology, Dec; 47(6):631-7, 2005.
  17. Inda MM, Fan X, Munoz J, Perot C, Fauvet D, Danglot G, Palacio A, Madero P, Zazpe I, Portillo E, Tunon T, Martinez-Penuela JM, Alfaro J, Eiras J, Bernheim A, Castresana JS. Chromosomal abnormalities in human glioblastomas: gain in chromosome 7p correlating with loss in chromosome 10q. Molecular Carcinogenesis, Jan;36(1):6-14, 2003.
  18. Mercapide J, Zhang SY, Fan X, Furio-Bacete V, Schneider J, Lopez de la Osa I, Patchefsky AS, Klein-Szanto AJ, Castresana JS. CCND1- and ERBB2-gene deregulation and PTEN mutation analyses in invasive lobular carcinoma of the breast. Molecular Carcinogenesis, Sep;35(1):6-12, 2002.