Professor of Neurosurgery and
Adjunct Professor of Oncological Sciences
B.S. University of Texas, Austin
M.D. University of Texas Southwestern Medical School, Dallas
Daniel Fults' Lab Page
Daniel Fults' PubMed Literature Search
Molecular Biology Program
Brain Tumor Biology
Medulloblastomas are malignant brain tumors that arise in the cerebellum in children. The cells of tumor origin are cerebellar neuron precursors, which proliferate rapidly during early postnatal development. Medulloblastomas result from mutations that perturb cell signaling pathways governing the growth and differentiation of neural stem cells. A barrier to improving patient treatment is collateral damage to the developing brain caused by radiation and chemotherapy. The overall objective of my research is to identify signaling molecules that induce medulloblastoma formation and to target these molecules therapeutically to maximize tumor growth suppression and minimize treatment-related neurotoxicity. To do this, we are using a mouse model of medulloblastoma that we developed using the RCAS/tv-a gene transfer system. This system utilizes a retroviral vector (RCAS), derived from avian leukosis virus (ALV), and a transgenic mouse line (Ntv-a) that produces TVA (the cell surface receptor for ALV) under control of the Nestin gene promoter. The Nestin gene is expressed by neural stem cells prior to their commitment to neuronal or glial differentiation. This system enables us to transfer and express exogenous genes in nestin-expressing neural stem cells inside the brain of live mice.
We showed that activation of the Sonic Hedgehog (Shh) signaling pathway in the developing cerebellum induces tumors in mice the closely resemble human medulloblastomas. Furthermore, we identified proteins that cooperate with Shh to enhance tumor formation. These enhancing factors are (a) Myc oncoproteins, which stimulate proliferation and survival of neural stem cells during normal development, (b) Bcl-2, which potently inhibits apoptosis, (c) insulin-like growth factor-II, which concomitantly stimulates proliferation and blocks apoptosis by activating the phosphatidylinositol 3-kinase signaling pathway, and (d) hepatocyte growth factor (HGF), a growth factor with pleiotropic effects on tumor growth.
We are also using this mouse model as a preclinical testing platform for therapies that specifically target Shh and HGF signaling. We showed that an HGF-neutralizing monoclonal antibody or a small molecule that inhibits Shh signaling significantly prolongs survival of mice, in which medulloblastomas are induced by RCAS-mediated transfer of Shh and HGF.
The current focus of the lab is to discover genes that cause medulloblastomas to disseminate from the cerebellum to the spinal leptomeningeal space, a condition that carries a grim prognosis for patients. Our approach is to use the RCAS/tv-a system to test candidate metastasis genes, which were identified via a mutagenesis strategy using the Sleeping Beauty transposon system.
- Jenkins NC, Kalra RR, Dubuc A, Sivakumar W, Pedone CA, Wu X, Taylor MD, and Fults DW. (2014) Genetic drivers of metastatic dissemination in sonic hedgehog medulloblastoma, Acta Neuropathologica Communications 2:85. PMID 25059231.
- Mumert M, Dubuc A, Wu X, North PA, Chin SS, Pedone CA, Taylor MD, and Fults DW. (2012) Functional genomics identifies drivers of medulloblastoma dissemination. Cancer Research 72:4944-4953. PMID 22875024.
- Wu X, Northcott PA, Dubuc A, Dupry AJ, Shih DJ, Witt H, Croul S, Bouffet E, Fults DW, Eberhart C, Garzia L, Van Meter T, Zagzag D, Jabado N, Schwartzentruber J, Majewski J, Scheetz TE, Pfister SM, Korshunov A, Li XN, Scherer SW, Cho YJ, Akagi K, McDonald T, Koster J, McCabe MG, Sarver AL, Collins VP, Weiss WA, Largaespada D, Collier LS, and Taylor MD. (2012) Clonal selection drives genetic divergence of metastatic medulloblastoma. Nature 482:529-533. PMID 22343890.
- Coon V, Laukert T, Pedone CA, Laterra J, Kim KJ, and Fults DW. (2010) Molecular therapy targeting sonic hedgehog and hepatocyte growth factor signaling in a mouse model of medulloblastoma. Molecular Cancer Therapeutics 9: 2627-2636. PMID 20807782.
- Binning MJ, Niazi T, Pedone CA, Lal B, Eberhart CG, Kim KJ, Laterra J, and Fults DW. (2008) Hepatocyte growth factor and sonic hedgehog expression in cerebellar neural progenitor cells costimulate medulloblastoma initiation and growth. Cancer Research, 66: 2666-2672. PMID 18829539.
- McCall TD, Pedone CA, and Fults DW. (2007) Apoptosis suppression by somatic cell transfer of Bcl-2 promotes medulloblastoma formation in mice. Cancer Research 67: 5179-5185. PMID 17545597.
- Browd SR, Kenney AM, Gottfried ON, Yoon JW, Walterhouse D, Pedone CA, and Fults DW. (2006) N-Myc can substitute for insulin-like growth factor signaling in a mouse model of sonic hedgehog-induced medulloblastoma. Cancer Research 66: 1-7. PMID 16510586.
- Rao G, Pedone CA, Del Valle L, Reiss K, Holland EC, and Fults DW. (2004) Sonic hedgehog and insulin-like growth factor signaling synergize to induce medulloblastoma formation from nestin-expressing neural progenitors in mice. Oncogene 23: 6156-6162. PMID 15195141.
- Rao G, Pedone CA, Coffin CM, Holland EC, and Fults DW. (2003) c-Myc enhances sonic hedgehog-induced medulloblastoma formation from nestin-expressing neural progenitors in mice. Neoplasia 5: 198-204. PMID 12869303.