Photo of Charles D. Stiles,  PhD

Charles D. Stiles, PhD

Dana-Farber Cancer Institute

Dana-Farber Cancer Institute
Phone: (617) 632-3512
Fax: (617) 632-4663


charles_stiles@dfci.harvard.edu

Charles D. Stiles, PhD

Dana-Farber Cancer Institute

EDUCATIONAL TITLES

  • Professor, Neurobiology, Harvard Medical School
  • Co-Chair, Cancer Biology, Dana-Farber Cancer Institute
  • Deputy Director, Mahoney Center for Neuro Oncology, Dana-Farber Cancer Institute

DF/HCC PROGRAM AFFILIATION

DF/HCC ASSOCIATIONS

  • 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

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  • Bergthold G, Bandopadhayay P, Hoshida Y, Ramkissoon S, Ramkissoon L, Rich B, Maire CL, Paolella BR, Schumacher SE, Tabak B, Ferrer-Luna R, Ozek M, Sav A, Santagata S, Wen PY, Goumnerova LC, Ligon AH, Stiles C, Segal R, Golub T, Grill J, Ligon KL, Chan JA, Kieran MW, Beroukhim R. Expression profiles of 151 pediatric low-grade gliomas reveal molecular differences associated with location and histological subtype. 2015. PubMed
  • Bergthold G, Bandopadhayay P, Bi WL, Ramkissoon L, Stiles C, Segal RA, Beroukhim R, Ligon KL, Grill J, Kieran MW. Pediatric low-grade gliomas: How modern biology reshapes the clinical field. Biochim Biophys Acta 2014; 1845:294-307. PubMed
  • Silbereis JC, Nobuta H, Tsai HH, Heine VM, McKinsey GL, Meijer DH, Howard MA, Petryniak MA, Potter GB, Alberta JA, Baraban SC, Stiles CD, Rubenstein JL, Rowitch DH. Olig1 function is required to repress dlx1/2 and interneuron production in Mammalian brain. Neuron 2014; 81:574-87. PubMed
  • Ramkissoon LA, Horowitz PM, Craig JM, Ramkissoon SH, Rich BE, Schumacher SE, McKenna A, Lawrence MS, Bergthold G, Brastianos PK, Tabak B, Ducar MD, Van Hummelen P, MacConaill LE, Pouissant-Young T, Cho YJ, Taha H, Mahmoud M, Bowers DC, Margraf L, Tabori U, Hawkins C, Packer RJ, Hill DA, Pomeroy SL, Eberhart CG, Dunn IF, Goumnerova L, Getz G, Chan JA, Santagata S, Hahn WC, Stiles CD, Ligon AH, Kieran MW, Beroukhim R, Ligon KL. Genomic analysis of diffuse pediatric low-grade gliomas identifies recurrent oncogenic truncating rearrangements in the transcription factor MYBL1. Proc Natl Acad Sci U S A 2013; 110:8188-93. PubMed
  • Liu X, Ide JL, Norton I, Marchionni MA, Ebling MC, Wang LY, Davis E, Sauvageot CM, Kesari S, Kellersberger KA, Easterling ML, Santagata S, Stuart DD, Alberta J, Agar JN, Stiles CD, Agar NY. Molecular imaging of drug transit through the blood-brain barrier with MALDI mass spectrometry imaging. Sci Rep 2013; 3:2859. PubMed
  • Meijer DH, Kane MF, Mehta S, Liu H, Harrington E, Taylor CM, Stiles CD, Rowitch DH. Separated at birth? The functional and molecular divergence of OLIG1 and OLIG2. Nat Rev Neurosci 2012; 13:819-31. PubMed
  • Chi AS, Batchelor TT, Dias-Santagata D, Borger D, Stiles CD, Wang DL, Curry WT, Wen PY, Ligon KL, Ellisen L, Louis DN, Iafrate AJ. Prospective, high-throughput molecular profiling of human gliomas. J. Neurooncol. 2012; 110:89-98. PubMed
  • Zhou J, Stiles CD. Asleep at the switch: MEK kinases control transit to gliogenesis in developing cortex. Neuron 2012; 75:940-2. PubMed
  • Sun Y, Meijer DH, Alberta JA, Mehta S, Kane MF, Tien AC, Fu H, Petryniak MA, Potter GB, Liu Z, Powers JF, Runquist IS, Rowitch DH, Stiles CD. Phosphorylation state of olig2 regulates proliferation of neural progenitors. Neuron 2011; 69:906-17. PubMed
  • Mehta S, Huillard E, Kesari S, Maire CL, Golebiowski D, Harrington EP, Alberta JA, Kane MF, Theisen M, Ligon KL, Rowitch DH, Stiles CD. The Central Nervous System-Restricted Transcription Factor Olig2 Opposes p53 Responses to Genotoxic Damage in Neural Progenitors and Malignant Glioma. Cancer Cell 2011; 19:359-71. PubMed
  • Chaponis D, Barnes JW, Dellagatta JL, Kesari S, Fast E, Sauvageot C, Panagrahy D, Greene ER, Ramakrishna N, Wen PY, Kung AL, Stiles C, Kieran MW. Lonafarnib (SCH66336) improves the activity of temozolomide and radiation for orthotopic malignant gliomas. J. Neurooncol. 2011. PubMed
  • Qin Y, Yao L, King EE, Buddavarapu K, Lenci RE, Chocron ES, Lechleiter JD, Sass M, Aronin N, Schiavi F, Boaretto F, Opocher G, Toledo RA, Toledo SP, Stiles C, Aguiar RC, Dahia PL. Germline mutations in TMEM127 confer susceptibility to pheochromocytoma. Nat Genet 2010; 42:229-33. PubMed
  • Wen PY,Yung WK,Lamborn KR,Norden AD,Cloughesy TF,Abrey LE,Fine HA,Chang SM,Robins HI,Fink K,Deangelis LM,Mehta M,Di Tomaso E,Drappatz J,Kesari S,Ligon KL,Aldape K,Jain RK,Stiles CD,Egorin MJ,Prados MD. Phase II study of imatinib mesylate (Gleevec(R)) for recurrent meningiomas (North American Brain Tumor Consortium Study 01-08). Neuro-oncol 2009; 11:853-60. PubMed
  • Fu H, Cai J, Clevers H, Fast E, Gray S, Greenberg R, Jain MK, Ma Q, Qiu M, Rowitch DH, Taylor CM, Stiles CD. A genome-wide screen for spatially restricted expression patterns identifies transcription factors that regulate glial development. J Neurosci 2009; 29:11399-408. PubMed
  • Sauvageot CM,Weatherbee JL,Kesari S,Winters SE,Barnes J,Dellagatta J,Ramakrishna NR,Stiles CD,Kung AL,Kieran MW,Wen PY. Efficacy of the HSP90 inhibitor 17-AAG in human glioma cell lines and tumorigenic glioma stem cells. Neuro-oncol 2008; 11:109-21. PubMed
  • MacConaill LE, Campbell CD, Kehoe SM, Bass AJ, Hatton C, Niu L, Davis M, Yao K, Hanna M, Mondal C, Luongo L, Emery CM, Baker AC, Philips J, Goff DJ, Fiorentino M, Rubin MA, Polyak K, Chan J, Wang Y, Fletcher JA, Santagata S, Corso G, Roviello F, Shivdasani R, Kieran MW, Ligon KL, Stiles CD, Hahn WC, Meyerson ML, Garraway LA. Profiling critical cancer gene mutations in clinical tumor samples. PLoS ONE 2009; 4:e7887. PubMed
  • Stiles CD,Rowitch DH. Glioma stem cells: a midterm exam. Neuron 2008; 58:832-46. PubMed
  • Sauvageot CM, Kesari S, Stiles CD. Molecular pathogenesis of adult brain tumors and the role of stem cells. Neurol Clin 2007; 25:891-924, vii. PubMed
  • Kesari S, Jackson-Grusby L, Stiles CD. "Smad"eningly erratic: target gene methylation determines whether TGFbeta promotes or suppresses malignant glioma. Dev Cell 2007; 12:324-5. PubMed
  • 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; 53:503-17. PubMed
  • 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, Hayes M, Letvak L, Egorin MJ, Capdeville R, Kaplan R, Murgo AJ, Stiles C, Prados MD. Phase I/II study of imatinib mesylate for recurrent malignant gliomas: North American Brain Tumor Consortium Study 99-08. Clin Cancer Res 2006; 12:4899-907. PubMed
  • Kesari S, Stiles CD. The Bad Seed: PDGF Receptors Link Adult Neural Progenitors to Glioma Stem Cells. Neuron 2006; 51:151-3. PubMed
  • 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; 103:7853-8. PubMed
  • 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; 292:152-64. PubMed
  • Kesari S, Ramakrishna N, Sauvageot C, Stiles CD, Wen PY. Targeted molecular therapy of malignant gliomas. Curr Oncol Rep 2006; 8:58-70. PubMed
  • 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; 65:9651-8. PubMed
  • 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; 5:14. PubMed
  • 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, Grossman A, Pigny P, Toledo SP, Nose V, Li C, Stiles CD. A HIF1alpha regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas. PLoS Genet 2005; 1:72-80. PubMed
  • Kesari S, Ramakrishna N, Sauvageot C, Stiles CD, Wen PY. Targeted molecular therapy of malignant gliomas. Curr Neurol Neurosci Rep 2005; 5:186-97. PubMed
  • Sauvageot C, Dahia PL, Lipan O, Park JK, Chang MS, Alberta JA, Stiles CD. Distinct temporal genetic signatures of neurogenic and gliogenic cues in cortical stem cell cultures. J Neurobiol 2004; 62:121-33. PubMed
  • 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; 306:2255-7. PubMed
  • 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; 306:2111-5. PubMed
  • Lu QR, Sun T, Zhu Z, Ma N, Garcia M, Stiles CD, Rowitch DH. Common developmental requirement for Olig function indicates a motor neuron/oligodendrocyte connection. Cell 2002; 109:75-86. PubMed
  • Alberta JA, Park SK, Mora J, Yuk D, Pawlitzky I, Iannarelli P, Vartanian T, Stiles CD, Rowitch DH. Sonic hedgehog is required during an early phase of oligodendrocyte development in mammalian brain. Mol Cell Neurosci 2001; 18:434-41. PubMed
  • Lu QR, Park JK, Noll E, Chan JA, Alberta J, Yuk D, Alzamora MG, Louis DN, Stiles CD, Rowitch DH, Black PM. Oligodendrocyte lineage genes (OLIG) as molecular markers for human glial brain tumors. Proc Natl Acad Sci U S A 2001; 98:10851-6. PubMed
  • Tekki-Kessaris N, Woodruff R, Hall AC, Gaffield W, Kimura S, Stiles CD, Rowitch DH, Richardson WD. Hedgehog-dependent oligodendrocyte lineage specification in the telencephalon. Development 2001; 128:2545-54. PubMed
  • Kim HA, Ratner N, Roberts TM, Stiles CD. Schwann cell proliferative responses to cAMP and Nf1 are mediated by cyclin D1. J Neurosci 2001; 21:1110-6. PubMed
  • Wang WL, Healy ME, Sattler M, Verma S, Lin J, Maulik G, Stiles CD, Griffin JD, Johnson BE, Salgia R. Growth inhibition and modulation of kinase pathways of small cell lung cancer cell lines by the novel tyrosine kinase inhibitor STI 571. Oncogene 2000; 19:3521-8. PubMed
  • Kim HA, Pomeroy SL, Whoriskey W, Pawlitzky I, Benowitz LI, Sicinski P, Stiles CD, Roberts TM. A developmentally regulated switch directs regenerative growth of Schwann cells through cyclin D1. Neuron 2000; 26:405-16. PubMed
  • Park JK, Williams BP, Alberta JA, Stiles CD. Bipotent cortical progenitor cells process conflicting cues for neurons and glia in a hierarchical manner. J Neurosci 1999; 19:10383-9. PubMed
  • Watson FL, Porcionatto MA, Bhattacharyya A, Stiles CD, Segal RA. TrkA glycosylation regulates receptor localization and activity. J Neurobiol 1999; 39:323-36. PubMed
  • Kim JY, Sutton ME, Lu DJ, Cho TA, Goumnerova LC, Goritchenko L, Kaufman JR, Lam KK, Billet AL, Tarbell NJ, Wu J, Allen JC, Stiles CD, Segal RA, Pomeroy SL. Activation of neurotrophin-3 receptor TrkC induces apoptosis in medulloblastomas. Cancer Res 1999; 59:711-9. PubMed
  • Dahia PL, Aguiar RC, Alberta J, Kum JB, Caron S, Sill H, Marsh DJ, Ritz J, Freedman A, Stiles C, Eng C. PTEN is inversely correlated with the cell survival factor Akt/PKB and is inactivated via multiple mechanismsin haematological malignancies. Hum Mol Genet 1999; 8:185-93. PubMed
  • Kwon YK, Bhattacharyya A, Alberta JA, Giannobile WV, Cheon K, Stiles CD, Pomeroy SL. Activation of ErbB2 during wallerian degeneration of sciatic nerve. J Neurosci 1997; 17:8293-9. PubMed
  • 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; 17:7007-16. PubMed
  • Alberta JA, Stiles CD. Phosphorylation-directed antibodies in high-flux screens for compounds that modulate signal transduction. Biotechniques 1997; 23:490-3. PubMed
  • 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; 18:553-62. PubMed
  • Reinertsen KK, Bronson RT, Stiles CD, Wang C. Temporal and spatial specificity of PDGF alpha receptor promoter in transgenic mice. Gene Expr 1997; 6:301-14. PubMed
  • Segal RA, Bhattacharyya A, Rua LA, Alberta JA, Stephens RM, Kaplan DR, Stiles CD. Differential utilization of Trk autophosphorylation sites. J Biol Chem 1996; 271:20175-81. PubMed
  • Freter RR, Alberta JA, Hwang GY, Wrentmore AL, Stiles CD. Platelet-derived growth factor induction of the immediate-early gene MCP-1 is mediated by NF-kappaB and a 90-kDa phosphoprotein coactivator. J Biol Chem 1996; 271:17417-24. PubMed
  • Segal RA, Pomeroy SL, Stiles CD. Axonal growth and fasciculation linked to differential expression of BDNF and NT3 receptors in developing cerebellar granule cells. J Neurosci 1995; 15:4970-81. PubMed
  • Guha A, Glowacka D, Carroll R, Dashner K, Black PM, Stiles CD. Expression of platelet derived growth factor and platelet derived growth factor receptor mRNA in a glioblastoma from a patient with Li-Fraumeni syndrome. J Neurol Neurosurg Psychiatry 1995; 58:711-4. PubMed
  • Guha A, Dashner K, Black PM, Wagner JA, Stiles CD. Expression of PDGF and PDGF receptors in human astrocytoma operation specimens supports the existence of an autocrine loop. Int J Cancer 1995; 60:168-73. PubMed
  • Freter RR, Alberta JA, Lam KK, Stiles CD. A new platelet-derived growth factor-regulated genomic element which binds a serine/threonine phosphoprotein mediates induction of the slow immediate-early gene MCP-1. Mol Cell Biol 1995; 15:315-25. PubMed
  • Segal RA, Goumnerova LC, Kwon YK, Stiles CD, Pomeroy SL. Expression of the neurotrophin receptor TrkC is linked to a favorable outcome in medulloblastoma. Proc Natl Acad Sci U S A 1994; 91:12867-71. PubMed
  • Shamah SM, Stiles CD, Guha A. Dominant-negative mutants of platelet-derived growth factor revert the transformed phenotype of human astrocytoma cells. Mol Cell Biol 1993; 13:7203-12. PubMed
  • Epstein RJ, Druker BJ, Roberts TM, Stiles CD. Synthetic phosphopeptide immunogens yield activation-specific antibodies to the c-erbB-2 receptor. Proc Natl Acad Sci U S A 1992; 89:10435-9. PubMed
  • Mercola M, Deininger PL, Shamah SM, Porter J, Wang CY, Stiles CD. Dominant-negative mutants of a platelet-derived growth factor gene. Genes Dev 1990; 4:2333-41. PubMed
  • Armelin HA, Armelin MC, Kelly K, Stewart T, Leder P, Cochran BH, Stiles CD. Functional role for c-myc in mitogenic response to platelet-derived growth factor. Nature 1984; 310:655-60. PubMed
  • Cochran BH, Reffel AC, Stiles CD. Molecular cloning of gene sequences regulated by platelet-derived growth factor. Cell 1983; 33:939-47. PubMed
  • Antoniades HN, Scher CD, Stiles CD. Purification of human platelet-derived growth factor. Proc Natl Acad Sci U S A 1979; 76:1809-13. PubMed
  • Stiles CD, Capone GT, Scher CD, Antoniades HN, Van Wyk JJ, Pledger WJ. Dual control of cell growth by somatomedins and platelet-derived growth factor. Proc Natl Acad Sci U S A 1979; 76:1279-83. PubMed
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