DF/HCC Program Affiliation

Co-Leader, Neuro-Oncology Program
Member, Cancer Cell Biology Program

DF/HCC Associations

Associate Director, Basic Science, EC
Member, Center Scientific Council

Research Abstract

The Stiles laboratory studies basic principles of growth factor signal transduction in nerve cells and in the developing nervous system. Two examples of work in progress are as follows: Growth Factor signal transduction through long axons. In myelinated nerve cells, target-derived neurotrophins must communicate with a nucleus that can be more than a meter away. In collaboration with Dr. Rosalind Segal (Dept. of Pediatric Oncology, DFCI) we are learning how target-derived neurotrophins transmit information through long nerve axons. Regulation of Neuronal Development by Platelet-Derived Growth Factor. Neurons, oligodendrocytes and astrocytes in the central nervous system are thought to be derived from a pluripotential stem cell in the embryonic neural plate. Our laboratory has shown that uncommitted stem cells from the developing cortex of embryonic rats develop into neurons following exposure to platelet-derived growth factor (PDGF). The laboratory is using adenoviral vectors to probe the signal transduction pathways that regulate this PDGF-mediated developmental switch. In addition, we are using subtractive hybridization methods to isolate PDGF-responsive gene sequences from the uncommitted stem cells.

Publications

• Kesari S, Jackson-Grusby L, Stiles CD. "Smad"eningly erratic: target gene methylation determines whether TGFbeta promotes or suppresses malignant glioma. Dev Cell 2007 Mar; 12(3):324-5
  PMID: 17336898
• Ligon KL, Huillard E, Mehta S, Kesari S, Liu H, Alberta JA, Bachoo RM, Kane M, Louis DN, Depinho RA, Anderson DJ, Stiles CD, Rowitch DH. Olig2-regulated lineage-restricted pathway controls replication competence in neural stem cells and malignant glioma. Neuron 2007 Feb 15; 53(4):503-17
  PMID: 17296553
• Wen PY, Yung WK, Lamborn KR, Dahia PL, Wang Y, Peng B, Abrey LE, Raizer J, Cloughesy TF, Fink K, Gilbert M, Chang S, Junck L, Schiff D, Lieberman F, Fine HA, Mehta M, Robins HI, DeAngelis LM, Groves MD, Puduvalli VK, Levin V, Conrad C, Maher EA, Aldape K,. Phase I/II study of imatinib mesylate for recurrent malignant gliomas: North American Brain Tumor Consortium Study 99-08. Clin Cancer Res 2006 Aug 15; 12(16):4899-907
  PMID: 16914578
• Kesari S, Stiles CD. The Bad Seed: PDGF Receptors Link Adult Neural Progenitors to Glioma Stem Cells. Neuron 2006 Jul 20; 51(2):151-3
  PMID: 16846849
• Ligon KL, Kesari S, Kitada M, Sun T, Arnett HA, Alberta JA, Anderson DJ, Stiles CD, Rowitch DH. Development of NG2 neural progenitor cells requires Olig gene function. Proc Natl Acad Sci U S A 2006 May 16; 103(20):7853-8
  PMID: 16682644
• Sun T, Hafler BP, Kaing S, Kitada M, Ligon KL, Widlund HR, Yuk DI, Stiles CD, Rowitch DH. Evidence for motoneuron lineage-specific regulation of Olig2 in the vertebrate neural tube. Dev Biol 2006 Apr 1; 292(1):152-64
  PMID: 16469306
• Kesari S, Ramakrishna N, Sauvageot C, Stiles CD, Wen PY. Targeted molecular therapy of malignant gliomas. Curr Oncol Rep 2006 Jan; 8(1):58-70
  PMID: 16464405
• Dahia PL, Hao K, Rogus J, Colin C, Pujana MA, Ross K, Magoffin D, Aronin N, Cascon A, Hayashida CY, Li C, Toledo SP, Stiles CD,. Novel pheochromocytoma susceptibility loci identified by integrative genomics. Cancer Res 2005 Nov 1; 65(21):9651-8
  PMID: 16266984
• Dahia PL, Ross KN, Wright ME, Hayashida CY, Santagata S, Barontini M, Kung AL, Sanso G, Powers JF, Tischler AS, Hodin R, Heitritter S, Moore F, Dluhy R, Sosa JA, Ocal IT, Benn DE, Marsh DJ, Robinson BG, Schneider K, Garber J, Arum SM, Korbonits M, Grossma. A HIF1alpha regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas. PLoS Genet 2005 Jul; 1(1):72-80
  PMID: 16103922
• McKee AE, Minet E, Stern C, Riahi S, Stiles CD, Silver PA. A genome-wide in situ hybridization map of RNA-binding proteins reveals anatomically restricted expression in the developing mouse brain. BMC Dev Biol 2005 Jul 20; 5:14
  PMID: 16033648
• Kesari S, Ramakrishna N, Sauvageot C, Stiles CD, Wen PY. Targeted molecular therapy of malignant gliomas. Curr Neurol Neurosci Rep 2005 May; 5(3):186-97
  PMID: 15865884
• Gray PA, Fu H, Luo P, Zhao Q, Yu J, Ferrari A, Tenzen T, Yuk DI, Tsung EF, Cai Z, Alberta JA, Cheng LP, Liu Y, Stenman JM, Valerius MT, Billings N, Kim HA, Greenberg ME, McMahon AP, Rowitch DH, Stiles CD, Ma Q. Mouse brain organization revealed through direct genome-scale TF expression analysis. Science 2004 Dec 24; 306(5705):2255-7
  PMID: 15618518
• Arnett HA, Fancy SP, Alberta JA, Zhao C, Plant SR, Kaing S, Raine CS, Rowitch DH, Franklin RJ, Stiles CD. bHLH transcription factor Olig1 is required to repair demyelinated lesions in the CNS. Science 2004 Dec 17; 306(5704):2111-5
  PMID: 15604411
• Bhattacharyya A, Watson FL, Bradlee TA, Pomeroy SL, Stiles CD, Segal RA. Trk receptors function as rapid retrograde signal carriers in the adult nervous system. J Neurosci 1997 Sep 15; 17(18):7007-16
  PMID: 9278536
• Williams BP, Park JK, Alberta JA, Muhlebach SG, Hwang GY, Roberts TM, Stiles CD. A PDGF-regulated immediate early gene response initiates neuronal differentiation in ventricular zone progenitor cells. Neuron 1997 Apr; 18(4):553-62
  PMID: 9136765
• Segal RA, Bhattacharyya A, Rua LA, Alberta JA, Stephens RM, Kaplan DR, Stiles CD. Differential utilization of Trk autophosphorylation sites. J Biol Chem 1996 Aug 16; 271(33):20175-81
  PMID: 8702742